Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[O:30]=[C:31]1[C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:41](O)=[O:42])[C:35]=2[CH2:34][CH2:33][N:32]1[CH:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:41]([C:36]1[C:35]2[CH2:34][CH2:33][N:32]([CH:44]([CH2:48][CH2:49][CH3:50])[CH2:45][CH2:46][CH3:47])[C:31](=[O:30])[C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:42])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cccc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cccc2C1=O
Reaction time: 24 h

Procedure:
Poured into a suspension of 150 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 101 mg of 1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 4 mg of hydroxybenzotriazole and 76 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 6 cm3 of dichloromethane is 0.217 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The solution is kept stirring for 24 h at a temperature close to 20° C. 15 cm3 of water are added to the reaction medium. The organic phase is washed with 5 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The product obtained is purified by flash chromatography over silica (column: 15 g; particle size: 120-40 μm, spherical; flow rate: 10 cm3/min; eluent: 100% ethyl acetate). After concentrating the fractions under reduced pressure, 140 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]-cyclopropyl}amino)propyl]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a colorless oil.
Reaction SMILES: S([C:5]1[CH:6]=[C:7]([C:14]([O-:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11])(O)(=O)=O.[Na+].[Na+].[Na+].[OH-:20].[Na+].C1(C(C2C=CC=C(C)C=2C)C)C=CC=CC=1>O>[OH:20][C:5]1[CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]
Reactant: [OH-]
Reactant: O=C([O-])c1cc(C(=O)[O-])cc(S(=O)(=O)O)c1
Agent: Cc1cccc(C(C)c2ccccc2)c1C
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(C(=O)O)c1
Temperature: 280 °C
Yield: 94.8 %

Procedure:
Trisodium 5-sulfoisophthalate (312 g) was added to 170 g of a 50% aqueous solution of sodium hydroxide, and the mixture was stirred. Then, 1980 g of 1-phenyl-1-(2,3-dimethylphenyl)-ethane was mixed, and the resulting mixture was heated to 280° C. in a nitrogen stream and dehydrated with stirring. The dehydrated mixture was stirred at 280° C. for 1.5 hours. After cooling, 1 liter of water was added to the reaction mixture to separate the reaction medium. The aqueous layer was decolorized with activated carbon, and precipitated with dilute sulfuric acid to give 172.5 g (yield 94.8%) of 5-hydroxyisophthalic acid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]1[CH2:26][C:24](=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21]C=2)[CH2:17]1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:8]2([C:23]3[C:18](=[CH:17][CH:16]=[CH:26][CH:24]=3)[CH2:19][CH2:20][CH2:21]2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC2(CCCc3ccccc32)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium in hexane, 25 mmol of α-tetralone and 70 mL of tetrahydrofuran. The product was recrystallized from ethyl acetate/diethyl ether (m.p. 117-119° C.). 1H NMR (CDCl3) δ 1.7-1.9 (m, 1 H), 1.9-2.1 (m, 2 H), 2.1-2.3 (m, 1 H), 2.7-3.0 (m, 2 H), 2.95 (d, 1 H), 3.1 (d, 1 H), 3.5 (s, 2 H), 7.1-7.2 (m, 1 H), 7.2-7.3 (m, 2 H), 7.4-7.5 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C.O>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:28]([C:27]2[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[O:29])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:7]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)c1c(C)cccc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)c1c(C)cccc1Cl
Reaction time: 15 h
Yield: 99.8 %

Procedure:
To a solution of 4-amino-N-[(2-chloro-6-methylphenyl)thioxomethyl]-L-phenylalanine methyl ester (3.57 mmol, 1.296 g) and 2,6-dichlorobenzoyl chloride (3.75 mmol, 0.785 g) in dichloromethane (20 mL) was added diisopropylethylamine (5.35 mmol, 0.93 mL) at room temperature. The solution was stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. After the addition of water (30 mL), the layers were separated and the aqueous phase was extracted with dichloromethane (20 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, 4:1 to 1:1) to obtain 1.91 g (83%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 535.0399. Calcd. mass, 535.0416 (M+H).
Reaction SMILES: [B].B(O)(O)[OH:3].[CH2:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH:6]1([OH:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:6]1(=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OB(O)O
Reactant: C1CCCCC1
Agent: [B]
Product: O=C1CCCCC1
Product: OC1CCCCC1

Procedure:
According to this invention, the refinement residue is the residue from the process comprising air oxidizing cyclohexane to KA oil in the presence of a boron compound such as boric acid to provide a crude product stream comprising cyclohexanol, cyclohexanone, cyclohexane and boric esters; and where the crude product stream is subjected to:
Reaction SMILES: O([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]([OH:26])=O)[CH:22]=2)[NH:17][CH:16]=1)=[O:11])C1C=CC=CC=1.C(N1[CH:38]=[CH:37]N=C1)(N1C=CN=C1)=O.[BH4-].[Li+].C(O)(=O)C.O1[CH2:49][CH2:48][CH2:47][CH2:46]1>>[C:38]1([CH2:8][O:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][OH:26])[CH:22]=3)[NH:17][CH:16]=2)[CH:37]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NCCc1c[nH]c2ccc(C(=O)O)cc12)OCOc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(=O)O
Product: O=C(NCCc1c[nH]c2ccc(CO)cc12)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of 3-[2-[[(phenoxymethoxy)carbonyl]amino]ethyl]-1H-indole-5-carboxylic acid (9 g) and carbonyldiimidazole (5.2 g) in dry tetrahydrofuran (THF) (150 ml) was stirred vigorously under nitrogen at room temperature for 5 h. A solution of lithium borohydride (1.6 g) in dry THF (70 ml) was added over 70 min and the mixture then stirred for 18 h. Aqueous acetic acid (30%, 25 ml) was added slowly to the ice-cooled mixture and the solution was then partitioned between brine (25%, 300 ml) and ethyl acetate (250 ml). The organic layer was washed with sulphuric acid (0.4M, saturated with sodium chloride, 3×80 ml), brine (100 ml) and potassium carbonate solution (25%, 2×100 ml). The dried (MgSO4) solution was evaporated in vacuo, the residue taken up in dichloromethane (150 ml) and insoluble material was filtered off. The filtrate was evaporated in vacuo to leave the alcohol (9 g) as a colourless oil containing some (ca. 45 mole %) ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH2:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([CH2:11][NH:12][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:22]([F:21])([F:32])[F:33])[CH2:9][CH2:10]2)=[N:6][CH:7]=1
Reactant: NCC1(c2ncc(Br)cc2Cl)CC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
3 g C-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropyl]-methylamine (step 3) was dissolved in 20 ml of dichloromethane and was cooled down to 0° C. 2.32 g of triethylamine was added, then a solution of 2.87 g 2-(trifluoromethyl)benzoyl chloride 5 ml dichloromethane was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours. Then water was added and the mixture was extracted twice with dichloromethane. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated. Crude material was obtained as a pale yellow sticky solid, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 4.74 g of N—[[1-(5-bromo-3-chloro-2-pyridyl)cyclopropyl]methyl]-2-(trifluoromethyl)benzamide was obtained as a colourless sticky solid. 1H-NMR (CDCl3): 8.45 ppm (s, 1H), 7.87 ppm (s, 1H), 7.65 ppm (d, 1H), 7.52 ppm (m, 2H), 7.41 ppm (d, 1H), 6.10 ppm (s, 1H, broad), 3.70 ppm (d, 2H), 1.10 ppm (m, 4H).
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:11]([OH:31])(=[O:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[OH:23]>C1(C)C=CC=CC=1>[C:11]([O-:31])(=[O:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[OH:23].[C:11]([O-:31])(=[O:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[OH:23].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)O
Solvent: Cc1ccccc1
Product: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)[O-]
Product: CCCC[Sn+2]CCCC

Procedure:
A mixture of dibutyltin oxide, 31.2 g (0.125 mole), ricinoleic acid, 74.25 g (0.25 mole), and 250 ml toluene were mixed and reacted as described in Example 1. Removal of toluene yielded 120 g (944 yield) of dibutyltin bis-ricinoleate, a yellow viscous liquid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.CS(O[CH2:29][CH2:30][C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38])(=O)=O>>[ClH:37].[Cl:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=1[CH2:30][CH2:29][N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)OCCc1c(Cl)cccc1Cl
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Product: Cl
Product: O=C(CCC1CCN(CCc2c(Cl)cccc2Cl)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Yield: 51.5 %

Procedure:
Using 8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (600 mg) and 2-(2,6-dichlorophenyl)ethyl methanesulfonate (545 mg) according to the same method as that of Example 81, the title compound (272 mg) was obtained as colorless crystals having a melting point of 226 to 229° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[N:14]=[C:13]([CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[CH:18][C:17]=2[Cl:23])[C:12]2[C:7](=[CH:8][C:9]([O:24][CH3:25])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl>[Cl:22][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([Cl:23])[C:16]=1[CH2:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:24][CH3:25])=[CH:10][CH:11]=2)[CH2:6][N:5]([C:3](=[O:4])[CH2:2][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:14]=1
Reactant: COc1ccc2c(c1)CN(C(=O)CCl)N=C2Cc1c(Cl)cncc1Cl
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CN(C(=O)CN1CCCC1)N=C2Cc1c(Cl)cncc1Cl
Yield: 55.9 %

Procedure:
A solution under N2 and stirring of 2-chloro-1-[4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1H-phthalazin-2-yl]-ethanone (1.3 g, 3.26 mmoles), prepared as described in example 81, in dry CHCl3 (15 ml) at room temperature was added with pyrrolidine (0.82 ml, 9.78 mmoles) and refluxed. After 20 hours the mixture was poured into water/ice, the phases separated, and the organic one washed with water, anhydrified and brought to dryness to give a residue which was crystallised from acetonitrile (40 ml) to give 0.79 g of the title compound (yield: 58%). m.p.: 148-150° C.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[OH-].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:36][C:33]2[CH:34]=[CH:35][C:30]([C:27]3[CH:28]=[CH:29][C:24]([O:23][C:22]([F:21])([F:37])[F:38])=[CH:25][CH:26]=3)=[CH:31][CH:32]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with 4′-Trifluoromethoxy-biphenyl-4-ol from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C26H25F3O6 [M+NH4]+: 508, [M+Na]+: 513.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([S:18][CH3:19])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][C:10]1[N:7]2[C:8]([CH3:9])=[C:3]([CH2:1][CH3:2])[C:4]([S:18][CH3:19])=[N:5][C:6]2=[N:12][C:11]=1[C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)C(=O)c1cn2c(C)c(CC)c(SC)nc2n1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(=O)c1nc2nc(SC)c(CC)c(C)n2c1Br
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
A solution of 1.0 g (3.63 mmol) of 1-(6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in 50 ml of chloroform was treated with 0.71 g (4.0 mmol) of N-bromosuccinimide. After 20 minutes at room temperature, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, 25 g: dichloromethane) to obtain 1.1 g (87%) of 1-(3-bromo-6-ethyl-5-methyl-7-methylthioimidazo[1,2-a]pyrimidin-2-yl)-2-methyl-2-propen-1-one in the form of pale yellow crystals melting at 87°-9° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1cccc(N)c1Br

Procedure:
2-Bromo-3-nitroanisole 1b3 (1.00 g; 4.31 mmol) was dissolved in glacial acetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2 (3×50 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline 1b4 (91%; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA) @ 220 nm: 95%
Reaction SMILES: [CH:1]([N:4]([CH:33]([CH3:35])[CH3:34])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])[CH:17]=[CH:18][C:19]=1[OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]>C(O)C.[Ni]>[NH3:4].[NH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]([OH:20])=[C:14]([C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:33]([CH3:34])[CH3:35])[CH:1]([CH3:3])[CH3:2])[CH:15]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOCCCCCC#N)ccc1O)C(C)C
Agent: [Ni]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOCCCCCCN)ccc1O)C(C)C
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-(4-{3-[(1R)-3-(Diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)hexanenitrile (Preparation 25, 783 mg, 1.64 mmol) was dissolved in ethanol (20 ml) and Raney nickel (100 mg) added. The reaction was hydrogenated under 60 psi at 40° C. for 18 hours, cooled to room temperature and the reaction filtered through Arbocel™ and the filtrate solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90/10/1.0 by volume) to furnish the title compound, 506 mg.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH2:28]O)[NH:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:20]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[S:40][CH2:28][C@H:10]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:30])[N:11]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(N[C@@H](CO)C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)[C@H]1CSC(c2ccccc2OCc2ccccc2)=N1

Procedure:
N-[2-(Benzyloxy)benzoyl]-L-serine benzyl ester (20 mg, 0.05 mmol) and Lawesson's reagent [2,4-bis(p-methoxyphenyl)-1,3-dithiadiphosphetane-2,4-disulfide] (20 mg, 0.05 mmol, 1 equiv.) were dissolved in toluene (15 mL). After being refluxed overnight under nitrogen, the reaction mixture was diluted with EtOAc (20 mL), washed with brine, dried over MgSO4, filtered, concentrated and chromatographed on silica gel eluting with hexanes/EtOAc (6/1) to yield thiazoline (7) as a clear oil. Rf=0.3 (hexanes/EtOAc, 6:1); 1H NMR (300 MHz, CDCl3) δ8.00 (dd, 1H, ArH), 7.51-7.49 (m, 2H, ArH), 7.42-7.25 (m, 9H, ArH), 7.02-6.95 (m, 2H, ArH), 5.28 (d, 1H, PhCHH), 5.20 (d, 1H, PhCHH), 5.18 (s, 2H, CH2Ph), 5.12 (dd, 1H, CHCH2), 3.60-3.47 (m, 2H, CHCH2); MS (FAB) m/z 404 MH+, measured exact mass: 404.1313, calculated exact mass: 404.1320.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[OH-].[K+]>CO>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:9]2[C:6]3[CH:7]=[N:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]=3[NH:11][CH:10]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN(C)c1cc2[nH]ccc2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1cc2[nH]cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2cn1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Dimethyl-(1H-pyrrolo[3,2-c]pyridin-6-yl)-amine (100 mg, 0.62 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (248 mg, 1.24 mmol) and potassium hydroxide (139 mg, 2.48 mmol) were added in MeOH (5 mL) and heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and poured into ice water (20 mL). The mixture was extracted with 10% MeOH/CH2Cl2 (5×10 mL). The organic extracts was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 0-5% MeOH/CH2Cl2) to obtain 180 mg (85%) of the title compound. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.58. MS (electrospray): exact mass calculated for C19H26N4O2, 342.21; m/z found, 343.2 (M++H). 1H NMR (CDCl3, 400 MHz): 9.09 (br s, 1H), 8.76 (s, 1H), 6.90 (d, J=2.15 Hz, 1H), 6.32 (s, 1H), 6.10 (br s, 1H), 4.10-4.05 (m, 2H), 3.62 (t, J=5.87 Hz, 2H), 3.03 (s, 6H), 2.52-2.44 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Clc1ncc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(Br)cn2)C1

Procedure:
According to the same method as in Example 1-1) but using 1-t-butoxycarbonyl-3-hydroxypyrrolidine and 2-chloro-5-bromopyrimidine, the entitled compound was obtained.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[C:12]([CH3:20])[CH:11]=1)[CH2:8][OH:9].C(N(CC)CC)C.C([O-])(C)(C)C.[K+]>C(#N)C.O>[Br:27][C:23]1[CH:22]=[C:21]([C:7]2([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:18])[F:19])=[C:12]([CH3:20])[CH:11]=3)[NH:6][C:3](=[O:4])[CH2:2][O:9][CH2:8]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(C(N)(CO)c2cccc(Br)c2)ccc1OC(F)F
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cc(C2(c3cccc(Br)c3)COCC(=O)N2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Chloroacetylchloride (1.81 ml, 1.2 eq) was added dropwise to a solution of (RS)-2-amino-2-(3-bromo-phenyl)-2-(4-difluoromethoxy-3-methyl-phenyl)-ethanol (intermediate VIII-4) (4.81 g, 1 eq) and triethylamine (2.78 ml, 1.5 eq) in acetonitrile (70 ml) at −2° C. After complete addition, the solution was left to warm to room temperature and stirring was continued for 5 hours. The reaction mixture was concentrated, washed with brine (3×20 ml), dried over sodium sulphate and concentrated in vacuo. The crude was dissolved in tert-butanol (50 ml), then treated in one portion with potassium tert-butanolate (4.9 g, 3.3 eq) and stirred at 35° C. overnight. The reaction mixture was then treated with water (50 ml) and extracted with ethyl acetate (3×20 ml). The combined organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel using a 9:1-mixture of cyclohexane and ethyl acetate as the eluent. The (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-morpholin-3-one was obtained as a white solid (4.5 g, 81% of theory). MS (ISP): m/z=413.8 [M+H]+.