Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([C:17]4[CH2:18][CH2:19][N:20](CC5C=CC=CC=5)[CH2:21][CH:22]=4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:30].[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([C:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CCN(Cc2ccccc2)C1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: C1=C(c2nc(C3=NOC(c4ccccc4)C3)cs2)CCNC1
Product: Cl
Temperature: 80 °C

Procedure:
To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1,2,3,6-tetrahydro-1-(phenylmethyl)pyridine (i.e. the product of Example 13, Step B) (0.400 g, 0.99 mmol) in dichloroethane (10 mL) was added 1-chloroethyl chloroformate (0.286 g, 1.99 mmol), and the reaction mixture was heated to 80° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Methanol (10 mL) was added to the residue, and the resulting mixture was heated to 60° C. for 1 h, cooled to room temperature, and concentrated under reduced pressure. The residue was triturated with 50% of petroleum ether in ethyl acetate, and the solid formed was filtered and dried to give 0.25 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH3:17])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18]I.[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[C:11]([CH2:17][CH3:18])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1nc(NC(=O)OC(C)(C)C)ccc1C#N
Yield: 77.3 %

Procedure:
To a stirred solution of 2-t-butoxycarbonylamino-5-cyano-6-methylpyridine (0.50 g, 2.145 mmol) in dry THF (15 ml) at -78° C. was added n-BuLl (1.75 ml, 2.5M in hexanes) dropwise. The solution turned deep red upon addition of the second equivalent of base. After 0.5 h methyl iodide (0.67 ml, 10.7 mmol) was added. After 1 h half saturated NH4Cl (15 ml) was added, the layers were separated and the aqueous layer was extracted with EtOAc (2×35 ml). The organic layers were combined and washed with saturated NaHCO3 (1×15 ml), water (1×15 ml), and brine (1×15 ml), dried over MgSO4, filtered and concentrated to an oil. The crude product was purified by flash column chromatography (95:5; hexanes: ethyl acetate) to give the title compound (0.41 g) as a solid: 1H NMR (CDCl3) δ 1.29 (t, J=7.5 Hz, 3 H), 1.53 (s, 9 H), 2.91 (q, J=7.6 Hz, 2 H), 7.40 (br s, 1H), 7.81 (d, J=8.6 Hz, 1 H), 7.87 (d, J=8.8 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][CH:10]2[N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:13]1[C:12]2([CH2:17][CH2:18][NH:19][CH:10]([CH2:9][NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH2:11]2)[CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1CNc1ccc(Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(NCC2CC3(CCCC3)CCN2)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
(±)tert-butyl 7-(((5-chloropyridin-2-yl)amino)methyl)-8-azaspiro[4.5]decane-8-carboxylate (intermediate 74, 1 g, 2.63 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0° C., then trifluoroacetic acid (30 ml) was added. After 1 hour at 0° C. and 2 hours at room temperature the solution was evaporated, the residue re-dissolved in dichloromethane was washed with saturated NaHCO3 aqueous solution. The organic layers were dried (Na2SO4) and concentrated under vacuum to obtain Obtained 600 mg of the title compound.
Reaction SMILES: [Mg].BrCCBr.C(Br)(C)C.[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([CH2:18][CH2:19][C:20]#[CH:21])=[O:17].C1(S([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][C@@H:33]([CH2:38][O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[O:32]2)(=O)=O)C=CC=CC=1>C1COCC1.[Zn+2].[Br-].[Br-]>[F:46][C:43]1[CH:42]=[CH:41][C:40]([O:39][CH2:38][C@H:33]2[O:32][C@H:31]([C:21]#[C:20][CH2:19][CH2:18][C:16]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][O:10]3)=[O:17])[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:45][CH:44]=1
Reactant: O=S(=O)(c1ccccc1)C1CCCC[C@@H](COc2ccc(F)cc2)O1
Reactant: C#CCCC(=O)C1CCCCO1
Agent: [Br-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CC(C)Br
Solvent: BrCCBr
Product: O=C(CCC#C[C@@H]1CCCC[C@@H](COc2ccc(F)cc2)O1)C1CCCCO1
Reaction time: 1 h

Procedure:
To a suspension of magnesium (0.58 g, 24.2 mmol) in dry THF (10 ml) was added catalytic 1,2-dibromoethane followed by dropwise addition of a soluton of isopropyl bromide (1.85 g, 15.1 mmol) in THF (5 ml). The reaction mixture was stirred for 1 hour and isoprpylmagnesiumbromide was cannulated into a 50 ml two-necked flask. A solution of 4-tetrahydropyranoyl-1-butyne (1.86 g, 12.0 mmol) in THF (5 ml) was added and the mixture was stirred for 30 minutes followed by addition of freshly prepared ZnBr2 solution (1 M, 7.25 ml, 7.2 mmol) in THF at 0° . After 45 minutes (2RS,7S)-2-(benzenesulfonyl)-7-(4-fluorophenoxymethyl)oxepane (2.2 g, 6.0 mmol) in THF (10 ml) was added and the mixture stirred for 30 hours. The reaction was quenched with saturated aqueous NH4Cl solution at 0° C. THF was removed under reduced preesure and the residue was portioned between EtOAc and water. The organic layer was washed with a brine, dried over Na2SO4 and concentrated to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetrahydropyranoyl-1-butynyl)oxepane. The crude product was dissolved in MeOH (25 ml) and 1% HCl in MeOH (5ml) was added. The hydrolysis of the THF group was completed in 2 hours and neutralized with saturated Na2CO3 solution and concentrated. The crude product was purified by silica gel chromatography using EtOAc-hexane (1:8) to give (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane (1.32 g, 75%); [α]D−74 (c 3.63, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.4-2.0 (m, 7H), 2.12 (m, 1H), 2.3 (s, 1H), 2.46 (dt, 2H), 3.65 (t, J=3.6 Hz, 2H), 3.74-3.97 (m, 2H), 4.51 (q, 1H), 6.8-7.0 (m, 4H); HRMS (EI): calcd. for C17H21O3F (M+) 292.147756 found 292.147473. Also, (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl)oxepane by similar procedure: [α]D+26.9 (c 2.2, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.48-2.03 (m, 8H), 2.2 (s, 1H), 2.47 (dt, 2H), 3.69 (t, J=6.9 Hz, 2H), 3.74-4.02 (m, 3H), 4.34 (dt, 2H), 6.78-7.0 (m, 4H).
Reaction SMILES: C1([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)C=CC=CC=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:12][C:10]3[SH:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:8][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC3=CC=C[SH]3c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 5-phenyl-2-thiophenecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 419.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([F:25])[C:8]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[C:9]([C:12]([NH:14][NH2:15])=[O:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.Br[C:27]#[N:28].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:28][C:27]1[O:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[C:7]([F:25])[C:8]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[N:5]=[N:4][CH:3]=[C:2]3[NH2:1])=[N:14][N:15]=1
Reactant: NNC(=O)c1cc2c(N)cnnc2c(F)c1Nc1ccc(Br)cc1F
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(-c2cc3c(N)cnnc3c(F)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-amino-7-(4-bromo-2-fluorophenylamino)-8-fluorocinnoline-6-carboxylic acid hydrazide (1.00 equiv.) in 1,4-dioxane at room temperature is added BrCN (2.00 equiv.) followed by a solution of NaHCO3 (1.00 equiv.) in H2O. After stirring for 3 hours at room temperature, the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to afford 6-(5-amino-[1,3,4]oxadiazol-2-yl)-N7-(4-bromo-2-fluoro-phenyl)-8-fluorocinnoline-4,7-diamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19](Cl)=[O:20])=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:26][O:25][N:24]([CH3:23])[C:19]([C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1)=[O:20]
Reactant: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1cc2cnc(SC)nc2n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride, 25, (1.02 g, 3.15 mmol) in CH2Cl2 (20 mL) is added N,O-dimethylhydroxylamine hydrochloride salt (0.37 g, 3.80 mmol) and triethylamine (1.32 mL, 9.50 mmol). The mixture is allowed to stir at room temperature for 16 hours. The reaction is diluted with H2O and extracted three times with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% to 40% EtOAc/hexanes) to afford 660 mg of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.90 (s, 1H), 7.44 (dd, J=8.4, 5.9 Hz, 2H), 7.22 (dd, J=8.4, 5.9 Hz, 2H), 7.10 (s, 1H), 3.62 (s, 3H), 3.26 (s, 3H), 2.54 (s, 3H); ESI+ MS: m/z (rel intensity) 347.0 (100, M++H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C@H:5]12[CH2:13][C@H:9]([O:10][C:11]1=[O:12])[CH:8]=[CH:7][CH2:6]2>O.C1COCC1>[N:1]([C@H:9]1[CH:8]=[CH:7][CH2:6][C@H:5]([C:11]([OH:12])=[O:10])[CH2:13]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1O[C@@H]2C=CC[C@H]1C2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H]1C=CC[C@H](C(=O)O)C1

Procedure:
A solution of 10.6 g of sodium azide in 70 ml of water is added to a solution of 18.4 g of racemic cis-6-oxabicyclo[3.2.1]oct-3-en-7-one in 175 ml of THF. The reaction mixture is then heated to reflux for 15 hours. The THF is subsequently stripped off in a rotary evaporator at a bath temperature of 30° C. The remaining aqueous phase is mixed with 165 ml of 2 molar sodium hydroxide solution and extracted twice with 110 ml of toluene each time and once with diethyl ether. The aqueous phase is then acidified with concentrated hydrochloric acid at about 10° C. The product is extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulphate, filtered and concentrated. 19.7 g of an oil, which becomes solid under storage in a refrigerator, are obtained. Assignment of the product to the trans isomer results from the experience that reactions of this type take place with inversion of the stereochemistry at the reaction site.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([CH:14]=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2].CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:14]([OH:18])=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)C12CCC(C=O)C(CC1)C2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C12CCC(C1)C(C(=O)O)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To an ice-cold solution of 4-formyl-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (3.85 mmol, 0.81 g) was added slowly Jones reagent (2.7 M, 1.43 mL). The reaction was stirred at ice temperature 20 min. then quenched by addition of iPrOH. diluted with H2O and extracted with Et2O (3×). The combined organic extracts were washed with H2O (2×). brine (1×), and dried (MgSO4). Filtration and evaporation provided the viscous oily bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.76 g, 87%) as a mixture of axial and equatorial acids. 13CNMR (100 MHz, CDCl3): 14.16 (q), 19.86 (t), 21.07 (t), 25.98 (t), 29.20 (t), 31.52 (t), 31.87 (t), 32.27 (t). 33.39 (t), 37.80 (d), 38.07 (t), 38.10 (d), 42.06 (t). 44.80 (d), 45.78 (d), 49.38 (s), 49.60 (s), 60.31 (t), 60.36 (t), 177.08 (s), 180.0.1 (s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:36]([O:40][CH3:41])(=[O:39])[CH:37]=[CH2:38]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:41][O:40][C:36](=[O:39])/[CH:37]=[CH:38]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2
Reactant: C=CC(=O)OC
Reactant: COc1ccc2cccc(Br)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1cccc2ccc(OC)nc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of 8-bromo-2-methyloxyquinoline (10.0 g), Pd(OAc)2 (311 mg), P(o-Tol)3 (1.28 g) in DMF (100 mL) was treated with TEA (17.6 mL) and methyl acrylate (18.93 mL). The solution was purged 3 times with nitrogen and stirred at 120° C. for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with ether/EA. The org. layer was washed with water (3×200 mL) and brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by CC (Hept/EA 4:1), affording a pale yellow solid (9.34 g; 91% yield).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([CH3:36])[N:30]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:29]=3[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:48]>ClCCl>[CH2:37]([N:30]1[C:29]2[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=3[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:14])=[C:19]([CH3:48])[CH:20]=3)=[O:25])[CH2:35][CH2:34][C:33]=2[N:32]=[C:31]1[CH3:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CC1
Reaction time: 20 h
Yield: 90 %

Procedure:
DIEA (0.176 ml, 1.02 mmol) and cyclopropanecarbonyl chloride (0.033 ml, 0.36 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (150 mg, 0.34 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 20 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give the title compound (155 mg, 90%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[NH:12]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.O>[CH2:20]([N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 4,6-dichloro-5-nitropyrimidine (7 g, 36 mmol) and TEA (10 mL, 72 mmol) in DCM (60 mL) at 0° C. under N2 was added Bn2NH in 10 mL dropwise over 2 hrs. Stirring was continued for 30 min before the reaction mixture was diluted with water (100 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4 and concentrated in vacuo. N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (12.8 g, 100%) was obtained as a brown slurry. LC-MS (ESI): m/z (M+1) 355.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1.[CH:25]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[CH:16]1([CH2:21][C:22]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:5])[N:32]([C:31]4[CH:33]=[CH:34][C:28]([CH:25]5[CH2:27][CH2:26]5)=[CH:29][CH:30]=4)[CH2:13][CH2:12]3)[CH2:11][CH2:10]2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: O=C(Cl)CC1CCCC1
Product: O=C(CC1CCCC1)N1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O

Procedure:
Off-white solid. MS (ESI): 381.25 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), cyclopentylacetyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: O(Cl)[Cl:2].[CH3:4][O:5][C:6](=[O:16])/[C:7](/C#N)=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[N:18]([CH:20]=O)[CH3:19]>>[CH3:4][O:5][C:6](=[O:16])[C:7]1[CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH:20]=[N:18][C:19]=1[Cl:2]
Reactant: CCCCC/C=C(\C#N)C(=O)OC
Reactant: ClOCl
Reactant: CN(C)C=O
Product: CCCCc1cnc(Cl)c(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 17 %

Procedure:
Phosporous oxychloride (4.76 ml, 51 mmol) was added within 10 minutes to an ice cold solution of (E)-2-cyano-oct-2-enoic acid methyl ester (4.65 g, 26 mmol) in DMF (12 ml) under an argon atmosphere. The reaction mixture was stirred for 14 h at 80° C. and poured onto ice water. After 3 h the mixture was extracted two times with dichloromethane, the combined extracts were washed with ice water and dried over sodium sulfate. Removal of the solvent under reduced pressure left a brown oil which was purified by column chromatography (silica gel, isopropyl acetate/heptane) to give 5-butyl-2-chloro-nicotinic acid methyl ester (1.01 g, 4.4 mmol; 17%) as yellow oil. MS: m/e=227.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH2:25])=[CH:22][CH:21]=[CH:20][CH:19]=2>CN(C)P(N(C)C)(N(C)C)=O.C(#N)C>[NH2:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Cc1ccc(C(=O)O)s1
Reactant: Nc1cnc2ccccc2c1N
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cnc3ccccc3c2N)s1
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 555 mg of 5-methylthiophene-2-carboxylic acid in 9 ml of anhydrous hexamethylphosphoramide and 0.9 ml of anhydrous acetonitrile is added dropwise 455 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 570 mg of 3,4-diaminoquinoline is added and stirred at 0°-5° C. for 4 hours. The same work-up as described in Example 1 gives 900 mg of 4-amino-3-(5-methylthien-2-ylcarbonylamino)quinoline B4 as a white solid. It is suspended in 15 g of polyphosphate ester and heated at 125° C. with stirring for 3 hours. The mixture is diluted with ice-water and neutralized with 1N sodium hydroxide and extracted with ethyl acetate. The extract is washed with water and saturated sodium chloride, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (10:1 v/v) as eluent to give 456 mg (48%) of C4 as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([O:24][C:25](=[O:28])[CH:26]=[O:27])[CH3:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:22]([O:24][C:25](=[O:28])[CH:26]([OH:27])[CH:15]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:2]([Br:1])[CH:3]=1)[C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH3:23]
Reactant: CCOC(=O)C=O
Reactant: CCCCC(=O)Cc1ccc(OC2CCCCC2)c(Br)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCC(=O)C(c1ccc(OC2CCCCC2)c(Br)c1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(3-Bromo-4-cyclohexyloxy-phenyl)-hexan-2-one (7.08 mmol, 2.5 g), oxo-acetic acid ethyl ester solution in toluene (2.8 mL, 50% solution in toluene) and triethylamine (0.5 mL) was stirred at ambient temperature for 16 h. The reaction mixture was diluted with DCM (300 mL), washed with water (3×100 mL), dried the organic layer and concentrated under reduced pressure. The resultant residue was purified by flash silica gel chromatography using mixture of hexanes in ethyl acetate (9:1) to provide 3-(3-bromo-4-cyclohexyloxy-phenyl)-2-hydroxy-4-oxo-octanoic acid ethyl ester (2.0 g).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH3:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C.O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[N:7]=[CH:6][CH:5]=[C:4]2[O:26][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([CH:16]([CH3:17])[CH3:15])=[CH:19][CH:20]=1
Reactant: CC(C)c1ccc(CCO)cc1
Reactant: Fc1cccc2c(Cl)ccnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CCOc2ccnc3c(F)cccc23)cc1
Reaction time: 8 h
Yield: 40.8 %

Procedure:
To a suspension of 0.96 g of sodium hydride in 10 mL of dry DMF was added 3.6 g of 4-chloro-8-fluoroquinoline. The mixture was cooled in an ice/water bath, and 3.3 g of 2-[4-(1-methylethyl)phenyl]ethyl alcohol was added. The mixture was stirred overnight, then diluted with ice and water. The pH was adjusted to 7, then the product was extracted into CH2Cl2. The CH2Cl2 layer was separated, filtered, and evaporated in vacuo. An azeotrope with xylene was formed to facilitate removal of residual DMF. The residue was chromatographically purified on a silica gel column, eluting with CH2Cl2, →5% EtOAc/CH2Cl2 →10% EtOAc/CH2Cl2. The fractions containing product were combined and evaporated to give an oil, which crystallized on adding ether. Recrystallization yielded 2.5 g of title product. M.P. 56°-60° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=[C:15]2[C:14]1=[O:24].[H][H]>[Rh]>[ClH:23].[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=[C:15]2[C:14]1=[O:24]
Reactant: [H][H]
Reactant: COCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Rh]
Product: COCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Product: Cl

Procedure:
The solution of 350 mg of N-(2-methoxymethyl-4-nitrophenyl)-4-chlorophthalimide is hydrogenated over 200 mg of 5% rhodium on carbon at 2.5 atmospheres of hydrogen pressure for 4 hours. After filtration from the catalyst, the residue is refluxed for 24 hours in 5 ml of xylene. After evaporation of the solvent, the residue is dissolved in acetone and the solution neutralized with ethereal hydrogen chloride, to yield the N-(2-methoxymethyl-4-aminophenyl)-4-chlorophthalimide hydrochloride melting at 255°-257°.