Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([Cl:11])=[CH:5][C:3]=1[NH:4][C:19](=[O:21])[CH3:20]
Reactant: COc1cc(Br)c(N)cc1Cl
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Br)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
4.40 g (18.6 mmol) 2-Bromo-5-chloro-4-methoxy-aniline and 3.1 ml (22.0 mmol) triethylamine were dissolved in 50 ml THF. 1.42 ml (20.0 mmol) acetylchloride were added dropwise at room temperature. The reaction mixture was stirred at room temperature for additional 2 hours, saturated NaHCO3 solution was added and the mixture was extracted with ethyl acetate. Removal of the solvent and crystallisation with ether gave 3.6 g (12.9 mmol, 69%) of the title compound.
Reaction SMILES: C(O)(=O)C.C(N=C1CC(C)CCN1)C.[ClH:15].[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH3:26])[CH:18]=1>>[ClH:15].[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][C:19](=[N:23][CH2:24][CH2:25][CH3:26])[CH2:18]1
Reactant: CCCNc1cc(C)ccn1
Agent: CCN=C1CC(C)CCN1
Agent: Cl
Solvent: CC(=O)O
Product: CCCN=C1CC(C)CCN1

Procedure:
The method of preparation of 2-(ethylimino)-4-methylpiperidine acetate was used to convert 4-methyl-2-(propylamino)pyridine hydrochloride to the title compound. The product was obtained as a clear colorless oil which crystallized under EtOAc. The analysis of the product was found to be consistent with the proposed structure. MH+=155; 1H NMR (D2O): 3.45-3.20 (m, 2H); 3.05 (t, J=6 Hz, 2H); 2.60-2.45 (m, 1H); 2.20-2.00 (m,; 1.95-1.70 (m, 2H); 1.60-1.40 (m, 2H); 1.40-1.25 (m, 1H); 0.90 (d, J=6 Hz, 3H); 0.80 (t, J=6 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]>>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Product: O=[N+]([O-])c1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-nitrobenzene: ESMS m/e: 238.2 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Cl.[CH3:18][NH:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([N:19]([OH:20])[CH3:18])=[NH:11]
Reactant: CNO
Reactant: N#Cc1ccccc1N1CCCCS1(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(O)C(=N)c1ccccc1N1CCCCS1(=O)=O
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(1,1-dioxo-1λ6-[1,2]thiazinan-2-yl)-benzonitrile and N-methylhydroxylamine hydrochloride (1.67 g, 20 mmol) in 1:1 water/ethanol (70 mL) was added sodium carbonate (1.06 g, 10 mmol) and the resulting mixture stirred at 90° C. for 18 h. After cooling and concentration, the resulting residue was suspended in MeOH/CHCl3 (100 mL, 1:9). The insoluble solids were removed by filtration and concentration of the filtrate gave the crude product as an amber oil (3.5 g) that was carried on without further purification. LCMS calcd for C12H17N3O3S (M+H): 284.35; found: 284.27.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[CH2:32]([CH:34]([CH2:37][CH3:38])[CH:35]=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:32]([CH:34]([CH2:37][CH3:38])[CH2:35][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)[CH3:33]
Reactant: CCC(C=O)CC
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCC(CC)CC)cc2)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
(±)-Cis-N-{1-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (75 mg, 0.145 mmol) in dichloromethane (3 mL) was added 2-ethylbutyraldehyde (26 uL, 0.2 mmol) in one portion. The mixture was stirred at room temperature for a 0.5 h before a solution of sodium triacetoxyborohydride (74 mg, 0.348 mmol) 1 ml DCM was added slowly. A single drop of acetic acid was added and the reaction was allowed to stir at room temperature over night. Excess reagent was quenched by the addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with 20 mL dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude product was purified by HPLC to afford the title compound (60 mg, 83%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[O:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:18][CH2:17]2)[CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[CH2:22]([CH:19]1[CH2:18][CH2:17][CH:16]([C@@H:13]2[CH2:14][O:15][C@@H:10]([CH2:9][OH:8])[O:11][CH2:12]2)[CH2:21][CH2:20]1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: [H][H]
Reactant: CCCCCC1CCC([C@H]2CO[C@H](COCc3ccccc3)OC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCC1CCC([C@H]2CO[C@H](CO)OC2)CC1

Procedure:
A solution of 100 mmol of trans/trans-2-benzyloxymethyl-5-(4-pentylcyclohexyl)-1,3-dioxane is hydrogenated in 300 ml of THF with the addition of 2.0 g of 5% Pd/activated charcoal until the take-up of hydrogen is complete. trans/trans-[5-(4-pentylcyclohexyl)-1,3-dioxan-2-yl]methanol is obtained by conventional work-up.
Reaction SMILES: [Si]([O:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)(C(C)(C)C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][N:50]1[C:59]2[C:54](=[CH:55][N:56]=[C:57]([CH3:60])[CH:58]=2)[CH:53]=[C:52]([C:61]2[CH:62]=[C:63]([NH:68]/[C:69](/[NH2:72])=[N:70]/O)[CH:64]=[CH:65][C:66]=2[CH3:67])[C:51]1=[O:73]>CN(C=O)C>[OH:8][C@@H:9]([C:10]1[O:12][N:70]=[C:69]([NH:68][C:63]2[CH:64]=[CH:65][C:66]([CH3:67])=[C:61]([C:52]3[C:51](=[O:73])[N:50]([CH3:49])[C:59]4[C:54]([CH:53]=3)=[CH:55][N:56]=[C:57]([CH3:60])[CH:58]=4)[CH:62]=2)[N:72]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: CC(C)[C@@H](O[Si](C)(C)C(C)(C)C)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: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc([C@H](O)C(C)C)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid (83 mg, 0.35 mmol) in DMF (2 mL) were added DIPEA (52 μL, 0.3 mmol) and HATU (0.11 g, 0.3 mmol). After stirring at rt for 15 min, 17 (0.10 g, 0.3 mmol) was added as a solution in DMF (1 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then was heated at 100° C. for 1 h. Subsequently, the reaction was cooled to rt, partitioned with EtOAc (30 mL) and 5% aq NaHCO3 (20 mL). The aqueous layer was extracted with fresh EtOAc (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and reduced to dryness. The crude material was dissolved in THF and was added TBAF (2.7 mL of a 1.0 M solution in THF). The mixture was stirred at rt for 2 h. Subsequently the reaction was diluted with EtOAc (20 mL) and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and reduced to dryness. The crude product was purified by preparative LCMS to give (R)-3-(5-(5-(1-hydroxy-2-methylpropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A92). 1H NMR (400 MHz, d6-DMSO) δ 9.87 (s, 1H), 8.81 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 7.39 (dd, J=8, 2 Hz, 1H), 7.30 (d, J=2 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.02 (d, J=6 Hz, 1H), 4.48 (bt, J=6 Hz, 1H), 3.67 (s, 3H), 2.61 (s, 3H), 2.07 (s, 3H) 0.94 (d, J=6 Hz, 3H), 0.87 (d, J=6 Hz, 3H). MS m/z 420.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[SH:26][CH2:27][CH2:28][OH:29]>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11][S:26][CH2:27][CH2:28][OH:29])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(OCCBr)c2ccc(Cl)cc2)cc1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: OCCSCCOC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 97.2 %

Procedure:
A solution of 2-[bis(4-chlorophenyl)methoxy]ethyl bromide (5.13 g, 14.2 mmol) in N,N-dimethylformamide (50 ml) was treated at 22° C. with powdered anhydrous potassium carbonate (3.0 g, 21.7 mmol) followed by 2-mercaptoethanol (1.25 g, 16.0 mmol). The resulting mixture was stirred at 22° for 18 h. The reaction mixture was then diluted with toluene (400 ml) washed with water, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel (elution ethyl acetate 0-10% in toluene) to give 4.93 g (96%) of the title material as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:17])=[N:14][C:15]=1[CH3:16]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7](=[S:8])[NH:17][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[C:15]([CH3:16])[N:14]=1)[CH3:2]
Reactant: Cc1nc(N)ccc1Br
Reactant: CCOC(=O)N=C=S
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Br)c(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethoxycarbonylisothiocyanat (7.71 g) was added to a stirred solution of 5-bromo-6-methylpyridin-2-amine (10.0 g) in dioxane (90 ml). The mixture was stirred for 2 h at r.t. A white solid precipitated. Hexane (100 ml) was added and the white solid was collected by filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1C=CC=CC=1)=[O:5].[CH:18]([C:21]1[N:22]=[C:23]([C:26](O)=[O:27])[S:24][CH:25]=1)(C)C.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:4]([C:3]1[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=1[NH:1][C:26]([C:23]1[S:24][CH:25]=[C:21]([CH3:18])[N:22]=1)=[O:27])(=[O:5])[CH3:6]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C)cs2)c1
Temperature: -30 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
Step E) To a suspension of 2.59 g (15.7 mmol) of 2-amino-4-methoxybenzophenone (product of step D) and 2.68 g (15.7 mmol) of 4-isopropylthiazole-2-carboxylic acid (product of step C) in 75 mL of pyridine cooled to −30° C., was added 1.93 mL (23.5 mmol) of POCl3 slowly dropwise over 5 min. The mixture was stirred 3 h, warmed to room temperature and was stirred overnite. The reaction mixture was poured into ice water, and extracted several times with EtOAc. The combined EtOAc extracts were dried (MgSO4), concentrated and chromatographed over SiO2 (eluted with 0% to 15% MeOH/EtOAc) to afford 2.57 g (51%) of 4-Methylthiazole-2-carboxylic acid (2-acetyl-5-methoxyphenyl)amide as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.41 (d, J=6.7 Hz, 6H), 2.64 (s, 3H), 3.24 (m, 1H), 3.91 (s, 3H), 6.67 (dd, J=9, 2.5 Hz, 1H), 7.18 (s, 1H), 7.86 (d, J=9 Hz, 1H), 8.56 (d, J=2.5 Hz, 1H), 13.48 (s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][C:37]=1[C:46]([F:49])([F:48])[F:47]>CN(C=O)C>[CH3:45][S:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])=[C:37]([C:46]([F:47])([F:49])[F:48])[CH:38]=1)(=[O:44])=[O:43]
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
To an ice-cooled solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((12.8 g, 62.8 mmol) in dry DMF (400 ml) under an inert atmosphere of Argon is added dropwise, BEMP (18.1 ml, 62.8 mmol) over two minutes. After stirring at 10° C. for 40 minutes, the resulting solution is treated dropwise with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (23.8 g, 75.4 mmol) and allowed to warm to room temperature while stirring overnight. The reaction is concentrated in vacuo with toluene azeotroping and the resulting oil is partitioned between water (400 ml) and DCM (500 ml) and extracted with DCM (500 ml). The organic portions are combined and washed with water (2×200 ml). The resulting suspension is filtered and concentrated in vacuo with toluene azeotroping. The crude is purified by chromatography on silica eluting with iso-hexane/acetone (16:4) to yield the titled product. (MH+ 441)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccccn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J7) (230 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (240 mg).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[N:6]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:8]1[C:7]([OH:12])=[N:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=1[OH:11])([O-:15])=[O:14]
Reactant: CCCSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1

Procedure:
According to U.S. Pat. No. 5,747,496, the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II is prepared by adding propyl iodide to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine in water containing sodium hydroxide; the reaction mixture is stirred for 2 weeks and then the reaction mass is concentrated to half volume; followed by the addition of hydrochloric acid and isolating the product by filtration to produce 2-propylthio-pyrimidine-4,6-diol. The 2-propylthio-pyrimidine-4,6-diol is then reacted with excess fuming nitric acid to produce 5-nitro-2-propylthiopyrimidine-4,6-diol. The 5-nitro-2-propylthiopyrimidine-4,6-diol is reacted with phosphoryl chloride in the presence of N,N-dimethylaniline at reflux to produce a reaction mass. The cooled reaction mass is poured onto ice followed by extracting with diethyl ether to afford a solution; then the combined extracts are dried and concentrated. The residue is chromatographed (SiO2, light petrol) to produce 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Cl:15][CH2:16][C:17]([CH3:19])=[CH2:18]>>[Cl:15][CH2:16][C:17]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([CH3:19])[CH3:18]
Reactant: COc1ccc(C)cc1
Reactant: C=C(C)CCl
Agent: O=S(=O)(O)O
Product: COc1ccc(C)cc1C(C)(C)CCl
Temperature: -78 °C
Reaction time: 18 h

Procedure:
To a yellow solution of 20 g of 4-methylanisole and 1.7 mL of concentrated sulfuric acid was added dropwise 19.17 mL of 3-chloro-2-methylpropene. The reaction became warm and turned dark purple and after 20 minutes a precipitate formed. The reactions was monitored by TLC indicating a new less polar product. After 18 hours, the reaction was poured onto ice and extracted with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to leave an oil. The residue was diluted with hexanes, cooled to −78° C., and the solids collected by filtration to afford 14 g of 2-(2-chloro-1,1-dimethylethyl)-1-methoxy-4-methylbenzene which melted upon warming to room temperature. The filtrate was concentrated in vacuo to afford 15.5 g of product and starting anisole (4:1 mixture).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].[NH:39]1[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]1.CS(C)(=O)=O>O1CCOCC1>[O:45]=[S:42]1(=[O:46])[CH2:43][CH2:44][N:39]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:40][CH2:41]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Reactant: O=S1(=O)CCNCC1
Agent: CS(C)(=O)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CCS(=O)(=O)CC3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1, thiomorpholine 1,1-dioxide was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 507.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:18][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: NC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CCCCC1
Yield: 61.5 %

Procedure:
51.5 g (0.27 mol) of 2,5-dichloronitrobenzene, 22.3 g (0.27 mol) of cyclohexylamine, 74.6 g (0.54 mol) of potassium carbonate and 0.5 g of 18-crown-6 in 300 ml of dimethylformamide were heated at 100° C. for 4 h. The mixture was then poured into water and extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was recrystallized from i-propanol, resulting in 42.3 g (62%) of the product. Melting point 101°-103° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([NH2:10])=[CH:8][CH:9]=1)=O.[NH4+:11].[OH-]>>[NH2:10][C:7]1[S:6][C:5]([C:3]([NH2:11])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(N)s1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)c1ccc(N)s1
Temperature: 60 °C
Yield: 47.4 %

Procedure:
A 18 ml vial was loaded with 5-amino-thiophene-2-carboxylic acid methylester (250 mg, 1.59 mmole) and 5 ml of 30% NH4OH. The vial was sealed and the mixture was heated at 60° C. for 24 hours. The mixture was cooled down and concentrated to give 200 mg crude product, 47.4% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])[CH:5]=[CH:4][N:3]=1.[C:22]1([C@@H:28]([NH2:30])[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O.CCOC(C)=O>[CH3:19][C:11]1([CH3:20])[O:10][C:9](=[O:21])[N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:30][C@H:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:29])[N:7]=2)[C@H:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)OC(=O)N(c2ccnc(Cl)n2)[C@H]1c1ccccc1
Reactant: C[C@H](N)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(N2C(=O)OC(C)(C)[C@@H]2c2ccccc2)n1)c1ccccc1
Yield: 85 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (33.9 mg, 0.112 mmol) and (S)-(−)-1-phenylethanamine (0.15 mL, 1.2 mmol, 10 equiv) in DMSO (1 mL) was heated at 110° C. for 140 min. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 50%) provided (S)-5,5-dimethyl-4-phenyl-3-(2-((S)-1-phenylethylamino)pyrimidin-4-yl) oxazolidin-2-one (37.0 mg, white solid) in 85% yield. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J=5.8 Hz, 1H), 7.43 (d, J=5.8 Hz, 1H), 7.31-7.24 (m, 3H), 7.19-7.11 (m, 5H), 7.01 (br s 2H), 5.48 (s, 1H), 4.86-4.80 (m, 1H), 1.65 (s, 3H), 1.43 (d, J=7.0 Hz, 3H), 0.98 (s, 3H); HRMS(B) m/z 389.1987 (M+H)+.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8].[NH3:19]>C(O)C>[NH2:19][CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: N
Reactant: CCOC(C)(OCC)P(=O)(C[C@H](O)CCl)OCC
Solvent: CCO
Product: CCOC(C)(OCC)P(=O)(C[C@H](O)CN)OCC
Yield: 19 %

Procedure:
A solution of ethyl (2S)-(3-chloro-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 6 days and at 55° C. for one further day. The solution was evaporated and the residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (5–8% MeOH) containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. The aqueous layer was pH adjusted by the addition of a few mL of 10% aqueous Na2CO3 and repeatedly extracted with methylene chloride. The combined organic layers were dried over Na2SO4 and evaporated to give 0.9 g (19%) of ethyl (2R)-(3-amino-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate as a clear oil. Data: 1H NMR (500 MHz, CDCl3) δ 4.1–4.3 (m, 2H), 4.05 (b, 1H), 3.60–3.80 (m, 4H), 2.4–2.9 (m, 2H), 1.7–2.1 (m, 2H), 1.4–1.5 (dd,3H), 1.3–1.4 (m, 3H), 1.2 (m, 6H).