Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.[CH3:32][NH2:33]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:33][CH3:32])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CN
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)cc1
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(C(=O)N(C)C)cc4)cnc3N)o2)cc1
Temperature: 100 °C
Yield: 19 %

Procedure:
4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (70 mg, 0.1460 mmol) was treated with methylamine (2 mL of 33% w/w solution in ethanol), and the resulting mixture stirred heated at 100° C. for 10 min. The reaction mixture was cooled to room temperature and filtered. The filtrate was collected and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were passed througha carbonate cartridge leuting with MeOH/CH2Cl2. The eluent was concentrated in vacuo and the solid triturated with acetonitrile to give the product as a yellow solid (11.4 mg, 19% yield); 1H NMR (400 MHz, DMSO) d 2.30 (s, 3H), 2.98-3.02 (m, 6H), 3.77 (s, 2H), 7.55 (d, 2H), 7.61 (d, 2H), 7.78 (br s, 2H), 8.11 (d, 2H), 8.17 (d, 2H) and 8.98 (s, 1H) ppm; MS (ES+) 430.31
Reaction SMILES: CON(C)[C:4]([C:6]1[NH:10][C:9]2[C:11]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])=[C:12]([CH3:14])[S:13][C:8]=2[CH:7]=1)=[O:5].[H-].[Na+].[CH3:28]OCCl.O>CN(C)C=O>[C:4]([C:6]1[NH:10][C:9]2[C:11]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])=[C:12]([CH3:14])[S:13][C:8]=2[CH:7]=1)(=[O:5])[CH3:28]
Reactant: CON(C)C(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of N-methoxy-N,2-dimethyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxamide (230 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60%, oily, 25 mg), and the mixture was stirred at room temperature for 30 min. Chloromethyl methyl ether (51 mg) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), methyl magnesium bromide (ca. 3.0M diethyl ether solution, 0.4 mL) was added thereto, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), 6N hydrochloric acid (5.0°mL) was added thereto, and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give N-(5-acetyl-2-methyl-4H-thieno[3,2-b]pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (55.2 mg, yield 26%) as gray crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 220° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]2)[CH:3]=1.[NH2:27][CH2:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[NH2:33][C:29]1([CH2:28][NH:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH:15]([CH3:26])[CH2:14]3)[CH:3]=2)[CH2:32][O:31][CH2:30]1
Reactant: NCC1(N)COC1
Reactant: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3Cc4ccccc4S(=O)(=O)C(C)C3)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 69-1 in Scheme 30 by using 4-(4-chloro-6-methylquinolin-2-yl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and 3-(aminomethyl)oxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 453, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (d, J=7.83 Hz, 1 H), 7.92 (brs, 1 H), 7.66 (s, 2 H), 7.52-7.41 (m, 2 H), 7.30 (dd, J=8.59, 1.77 Hz, 1 H), 6.19 (s, 1 H), 5.18 (brs, 1 H), 5.10 (brs, 1 H), 4.66-4.55 (m, 4 H), 3.68 (d, J=2.02 Hz, 2 H), 3.65-3.57 (m, 1 H), 3.35-3.30 (m, 3 H), 2.43 (s, 3 H), 1.60-1.40 (brs, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.COCCOC.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:21]=[CH:20][N:19]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccc(F)cc1
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A reaction vessel was charged with 0.255 g of tetrakistriphenylphosphine palladium, 1.132 g of 4-fluorophenylboronic acid, and 3.122 g of tripotassium phosphate n-hydrate, to which 36 ml of 1,2-dimethoxyethane, 9 ml of water, and 1.095 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 8 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.399 g of 4-chloro-6-(4-fluorophenyl)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[N:6]([CH2:12][CH3:13])[C:5]2=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([CH2:12][CH3:13])[CH2:5]2
Reactant: CCN1C(=O)c2ccc(Br)cc2C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
To a solution of 5-bromo-2-ethylisoindoline-1,3-dione (1.27 g, 5 mmol) in THF (10 mL) was added LAH (1 M in THF, 12.5 mL, 12.5 mmol) dropwise over 10 min. The reaction was exothermic. After addition, the resulting mixture was stirred for 30 min at rt. LC-MS showed over reduction. The reaction was quenched with sat. NH4Cl, basified with sat. NaHCO3 and the product was extracted with EtOAc. The mixture was purified by flash chromatography (gradient: MeOH/DCM 0 to 15%) to give the crude 5-bromo-2-ethylisoindoline as a light yellow oil (120 mg). The crude material was converted to the title compound (73 mg, impure, 5% over 2 steps) as a light brown oil using the method for the preparation of Example A51A. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J=18.4 Hz, 1H), 7.31 (s, 1H, partially overlapping with the peak at 7.30 ppm), 7.30 (d, J=8.0 Hz, 1H, partially overlapping with the peak at 7.31 ppm), 7.13 (d, J=7.6 Hz, 1H), 6.10 (d, J=18.4 Hz, 1H), 3.88 (s, 4H), 1.29 (s, 12H).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]3[C:13]=2[C:14](=[O:26])[N:15]([C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[N:16]=3)[CH2:3][CH2:2]1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>O1CCCC1>[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH:32][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([N:15]2[C:14](=[O:26])[C:13]3=[C:4]([CH:1]4[CH2:3][CH2:2]4)[NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]3=[N:16]2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4ccccc4[nH]c(C4CC4)c-3c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a partial solution of 4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoyl chloride (0.1 g, 0.28 mmol) in tetrahydrofurane (6 ml) under nitrogen was added a solution of 3-dimethylamino-propyl amine (0.03 g, 0.3 mmol) in tetrahydrofurane (3 ml). The mixture was stirred at RT for 3 h. The solvent was removed under reduced pressure and the yellow solid was washed with a little saturated sodium bicarbonate, water and dried under vacuo to yield N-(3-Dimethylamino propyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl]-benzamide (57 mg, 47%) as a yellow solid. LCMS m/z 430.11 [M+H]+ @ RT 0.99 min: 100% purity.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([OH:27])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][N:3]=1.Br[CH2:29][CH2:30][CH3:31]>>[CH2:17]([O:16][C:14]1[C:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:12]([O:27][CH2:29][CH2:30][CH3:31])[CH:11]=[C:10]([CH2:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:15]=1)[CH3:18]
Reactant: CCCBr
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(OC)cc1
Product: CCCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(OC)cc1

Procedure:
Starting from 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-4′-methoxy-biphenyl-2-ol (200 mg; 0.545 mmol) and 1-bromopropane (0.060 ml; 0.654 mmol), 121 mg (454%) 5-(6-ethoxy-4′-methoxy-2-propory-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a colourless powder.
Reaction SMILES: [Br-].[C:2]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.[CH3:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=O>CS(C)=O>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([C:27]([CH3:2])=[CH2:26])=[CH:30][CH:31]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CS(C)=O
Product: C=C(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of triphenylphosphonium bromide (17.94 g, 50.24 mmol) in DMSO (10 ml) was added n-BuLi (39.25 ml, 1.6M solution in hexane, 62.80 mmol). The solution was stirred at rt for 1 h and to this was added a solution of 4-bromoacetophenone (10.00 g, 50.24 mmol) in DMSO (4 ml). The reaction mixture was then stirred at rt overnight and then quenched with water and the product was extracted with pentane. The organic layers were combined washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by filtration through a short pad of silica using pentane as eluant to give 1-bromo-4-isopropenylbenzene (5.23 g, 53%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.45 (d, J=9.0 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 5.36 (m, 1H), 5.10 (m, 1H), 2.12 (m, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](I)=[CH:14][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:25]3[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=3)=[CH:14][C:13]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(I)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccn3C)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-ethyl-3-(7-iodo-5-pyridin-3-yl-benzothiazol-2-yl)-urea (0.10 g, 0.24 mmol) in DMF (2.0 mL) was added N-methyl-2-tributylstannyl-1H-pyrrole (0.18 g, 0.47 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.027 g, 0.024 mmol). The reaction mixture was again degassed for half an hour and then heated at 120° C. for 20 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off, added water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep-HPLC to provide the title compound as off white solid (0.005 g, 6.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[NH:12][C:11]3[CH:17]=[CH:18][C:19]([CH2:21][O:22][C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:10]=3[S:9]2)=[CH:4][CH:3]=1.Cl.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:14]([OH:15])[C:13](=[O:16])[N:12]([CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])[C:11]3[CH:17]=[CH:18][C:19]([CH2:21][O:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:20][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc([C@@H]2Sc3cc(COC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc([C@@H]2Sc3cc(COC(c4ccccc4)(c4ccccc4)c4ccccc4)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 92.6 %

Procedure:
A mixture comprising 2.48 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-8-trityloxymethyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.75 g of 2-(dimethylamino)ethyl chloride hydrochloride, 1.70 g of potassium carbonate and 50 ml of acetone was refluxed overnight while stirring. After the mixture was cooled, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residual was recrystallized from a mixed solution of ethyl acetate and n-hexane to give 2.59 g of (-)-cis-2-(4-methylphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-trityloxymethyl-2,3-dihydro-1,5-benzothiazepin-4(5H) -one.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=O)[C:4](O)=[CH:3][CH:2]=1.[C:10]1([CH3:20])[CH:15]=CC(S(Cl)(=O)=O)=C[CH:11]=1>N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:8]=[CH:7]2)[CH:11]=1
Reactant: O=c1cccccc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1cc2cccccc-2c1

Procedure:
2-Methylazulene was synthesized according to a method described in Japanese Patent Laid-Open Publication No. 207232/1987. Specifically, 19.5 g (0.16 mol) of tropolone was reacted with 40 g (0.21 mol) of p-toluenesulfonic acid chloride in pyridine to give 37.1 g of tosylated tropolone. Then, 20 g (0.15 mol) of dimethylmalonate was reacted with 9.7 g (0.18 mol) of NaOMe in methanol at room temperature for 4 hr to give 14.4 g of 3-methoxycarbonyl-2H-cyclohepta(b) furan-2-one (Compound (2)). Then, 12 g of Compound (2), 200 ml of acetone and 70 ml of diethylamine were added, and the mixture was heated under reflux for 30 hr. Thereafter, H2O was added thereto, and the mixture was extracted with toluene to give 39.2 g of methyl-2-methylazulene carboxylate. Further, 25 ml of phosphoric acid was added, and a reaction was allowed to proceed at 85° to 90° C. for one hr. The reaction mixture was decomposed with water, extracted with benzene and dried to give 6.5 g of 2-methylazulene as an intended product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[BrH:12]>Br.C(O)(=O)C>[BrH:12].[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:12])[N:3]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Product: Nc1nc(Br)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 4 h

Procedure:
2-Amino-6-chloro-3-nitropyridine (20.2 g) was suspended in a 30% hydrobromide/acetic acid solution (100 ml), and the suspension was stirred at 90° C. After 4 hours, a 30% hydrobromide/acetic acid solution (100 ml) was added, and the mixture was stirred for another 1 hour at 90° C. Then, the reaction mixture was stirred at 100° C. for 8 hr while a hydrobromic acid gas was introduced little by little. The reaction mixture was cooled, and the precipitate was collected by filtration and washed with hexane to give the objective compound (33.0 g) as a pale-yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Li]CCCC.[CH3:26][C:27]([S@:30](/[N:32]=[C:33](/[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)\[C:34]([F:37])([F:36])[F:35])=[O:31])([CH3:29])[CH3:28].[NH4+].[Cl-]>C1COCC1>[C:27]([S@:30]([NH:32][C@:33]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:34]([F:35])([F:36])[F:37])=[O:31])([CH3:29])([CH3:26])[CH3:28]
Reactant: CC(C)(C)[S@@](=O)/N=C(/c1ccc(F)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc([C@@](N[S@](=O)C(C)(C)C)(c3ccc(F)cc3)C(F)(F)F)cn2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
tert-Butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (0.242 g, 0.705 mmol) was taken up in THF (3.5 mL) and cooled to −78° C. A solution of nBuLi, 2.5 M in hexanes (0.31 mL, 0.775 mmol) was added at a fast dropwise rate from a syringe. The resulting mixture was stirred at −78° C. for 15 minutes. A solution of (R,Z)-2-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethylidene)propane-2-sulfinamide (0.225 g, 0.762 mmol) in THF (0.5 mL) was added at a fast dropwise rate from a syringe. The reaction mixture was stirred at −78° C. for 5 minutes before warming to room temperature. After 45 minutes, saturated NH4Cl was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by MPLC (0-80% EtOAc-hexanes) gave tert-butyl 4-(5-((S)-1-(((R)-tert-butylsulfinyl)amino)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (304 mg, 0.543 mmol, 77% yield) as a pale yellow gum. The absolute stereochemistry was assigned randomly.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH2:16]O)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18]CCl.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>O.N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([CH2:16][Cl:18])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)cc(CO)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)cc(CCl)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69 %

Procedure:
To a mixture of 0.74 g (2.9 mmol) of 2-(t-butoxycarbonyl)amino-4-chloro-6-hydroxymethylpyridine and 20 mL of dichloromethane 20 mL, 0.29 g (3.7 mmol) of pyridine was added, and 0.41 g (3.5 mmol) of thionyl chloride was further added, followed by stirring at room temperature for 3.5 hours. The reaction solution was added to water and saturated sodium bicarbonate aqueous solution was added thereby adjusting the pH to 6, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 (v/v)) to obtain 0.56 g (2.0 mmol, yield of 71%) of 2-(t-butoxycarbonyl)amino-4-chloro-6-chloromethylpyridine.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].[CH3:13][C:14]([CH3:16])=O.N1CCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.N1CCCC1>[CH3:11][O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:12][C:14]([CH3:16])([CH3:13])[CH2:1][C:2]2=[O:3]
Reactant: COc1ccc(O)c(C(C)=O)c1
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: COc1ccc2c(c1)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
A mixture of 48.9 g (0.294 mole) 2-hydroxy-5-methoxyacetophenone, 32 mL (0.441 mole) acetone and 12 mL (0.147 mmole) pyrrolidine in 300 mL toluene was stirred at room temperature for 3 hours, then refluxed over a Dean-Stark trap for 3 hours. An additional 32 mL (0.441 mole) acetone and 12 mL (0.147 mole) pyrrolidine was added and the mixture again refluxed over the Dean-Stark trap for 18 hours. The mixture was concentrated, poured into water, basified, and extracted with ether. The ether extract was, washed with 1N KOH, water and brine and then dried (MgSO4) and concentrated to give an oil. Flash chromatography on silica gel with 20% ethyl acetate in hexanes afforded a solid. Recrystallization from ether/hexanes yielded 32.0 g (53%) of pure product. mp 71°-73° C. Analysis calculated for C12H14O3 : C, 69.89; H, 6.84. Found: C, 69.85; H, 7.08.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH3:18]>C(O)C>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[C:3]1[N:4]=[C:5]([NH2:18])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: N
Reactant: Clc1ccc(Cl)c(-c2nc3ccccc3[nH]2)n1
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)n1
Reaction time: 16.67 h
Yield: 21 %

Procedure:
2-(3,6-Dichloro-pyridin-2-yl)-1H-benzoimidazole (20 mg; 0.076 mmol) was dissolved in ethanol (1.5 ml) and concentrated ammonia (2 ml) in a pressure tube. After 1000 minutes in a microwave at 140° C. and 200 psi, the solvents were removed and the residue dissolved in isopropyl alcohol (1 ml) and concentrated ammonia (1 ml) before microwaving as before. The solvents wore evaporated and the residue chromatographed on silica gel with 80% ethyl acetate in heptane to give 6-(1H-benzoimidazol-2-yl)-5-chloro-pyridin-2-ylamine (4 mg, 21%).
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][N:38]2C(=O)C3=CC=CC=C3C2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN>ClCCl.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][C@H:13]2[CH2:37][NH2:38])=[O:11])=[CH:49][CH:50]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-tritylthiopyrrolidine (10.46 g: 15.31 mmole) in a mixture of dichloromethane (80 ml) and methanol (160 ml), hydrazine hydrate (1.53 ml: 2 eq.) is added, and the mixture is concentrated to remove dichloromethane by warming and refluxed for 3 hours and 15 minutes. The reaction mixture is concentrated in vacuo. The residue is diluted with dichloromethane and filtered to remove solid. The filtrate is washed with water, dried over magnesium sulfate, and concentrated in vacuo to give crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-tritylthiopyrrolidine (7.71 g). Yield: 91%.