Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[C:8]1(=[O:14])[O:13][C:11](=[O:12])[CH:10]=[CH:9]1>C(Cl)Cl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12]
Reactant: COC(CN)OC
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Product: COC(CNC(=O)/C=C\C(=O)O)OC
Yield: 79.2 %

Procedure:
Aminoacetaldehyde dimethyl acetal (90 g, 0.857 mol) was added over 45 min to a 16° C. mixture of 84 g (0.857 mol) of purified maleic anhydride (azeotropic removal of H2O by distillation of xylene from crude anhydride) in 855 mL of CH2Cl2 (reaction temperature below 30° C.). After 1 h all of the amine had reacted and the solvent was removed on a rotary evaporator to yield a yellow solid. Recrystallization from MeOH gave 138 g (75% yield) of white solid, mp 91°-92° C. Further recrystallization (toluene/MeOH) gave mp 93°-94.5° C.
Reaction SMILES: [I:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:15]2([OH:19])[CH2:18][O:17][CH2:16]2)=[N:4][C:3]=1[CH3:20].[H-].[Na+].[CH3:23]I>O1CCCC1>[I:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([C:15]2([O:19][CH3:23])[CH2:18][O:17][CH2:16]2)=[N:4][C:3]=1[CH3:20]
Reactant: CI
Reactant: Cc1nc(C2(O)COC2)n(COCC[Si](C)(C)C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2nc(C)c(I)n2COCC[Si](C)(C)C)COC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.6 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.3, 800 mg, 1.95 mmol) in tetrahydrofuran (30 mL). This was followed by the addition of sodium hydride (156.2 mg, 3.9 mmol, 60%) at 0° C. and stirred for 20 min at room temperature. To this was added CH3I (554.1 mg, 3.90 mmol) at 0° C. The resulting solution was stirred for 5 h at room temperature, then quenched with 30 mL of Na2S2O3 (sat.). The aqueous phase was extracted with 3×40 mL of ethyl acetate, the combined organic layers were washed with 3×40 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:2) eluent to furnish 700 mg (85%) of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[N:22]=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([F:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:21]1[N:22]=[C:17]([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)n1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl [6-(2-{3-[(2-chloro-5-fluoropyrimidin-4-yl)amino]phenyl}ethyl)pyridin-2-yl]carbamate (215 mg, 0.48 mmol) in 1,4-dioxane (0.90 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (4.5 mL). The resultant reaction mixture was stirred at 35° C. for 3 hours. The reaction mixture was concentrated under vacuum to give the desired product as a very hydroscopic light yellow powder (194 mg, 96%). LCMS for C17H16ClFN5 (M+H)+: m/z=344.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[NH:4][C:3]1=S.[NH:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH2:18]>C(O)C>[CH3:1][C:2]1([CH3:16])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[N:4]=[C:3]1[NH:18][NH:17][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)NN
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=S
Solvent: CCO
Product: CCOC(=O)NNC1=Nc2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 86.8 %

Procedure:
2,2-Dimethyl-6-nitro-2H-benzo[b][1,4]oxazine-3(4H)-thione (3 g) and ethyl hydrazinecarboxylate (3.94 g, 3.0 eq.) were suspended in ethanol (50 ml). The reaction mixture was refluxed for 6 hours. The yellow precipitation was filtered and washed with ether to give ethyl 2-(2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3-yl)hydrazine-1-carboxylate (3.37 g, 87% yield).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>O1CCOCC1>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([C:28]3[NH:27][CH:31]=[CH:30][N:29]=3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Solvent: C1COCCO1
Product: O=S1CCN(c2nc(-c3ncc[nH]3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido[5,4-d]pyrimidine and imidazole by refluxing for six hours in dioxane.
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.[P:10]([OH:13])([OH:12])[OH:11].Cl.C=O>>[P:10]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:13])([OH:12])=[O:11]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: OP(O)O
Agent: C=O
Agent: Cl
Product: CN(CC(=O)O)CP(=O)(O)O
Temperature: 120 °C
Reaction time: 19 h
Yield: 99 %

Procedure:
N-acetyl sarcosine (XX) (20.0 g, 152.5 mmole), phosphorous acid (12.5g, 152.4 mmole), and concentrated HCl (37.6 g) were mixed and refluxed in a 120° C. oil bath. Formalin, 37% (13.6 g, 167.6 mmole) was added dropwise over 20 min. and the reaction was continued for an additional 19 h. HPLC analysis indicated a 99% yield of N-methylglyphosate (XXI) based on moles of (XX) charged.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH:11]=O)[CH2:3]1.C[C:15]1[NH:16]C2C(C=1C=O)=CC=CC=2>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][NH:16][CH3:15])[CH2:3]1
Reactant: CC1(C)CC(C=O)c2ccccc21
Reactant: Cc1[nH]c2ccccc2c1C=O
Product: CNCC1CC(C)(C)c2ccccc21
Yield: 81 %

Procedure:
According to the procedure of Preparation 12, except substituting 1,1-dimethyl-3H-indene-3-carboxaldehyde for the 2-methylindole-3-carboxaldehyde, the title compound (3 g, 81%) was obtained as a reddish oil: MS (ES) m/e 188.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([O:18]C)=[O:17])=[CH:5]2.[OH-].[K+].CCO.CC(O)=O.Cl>CCO.O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](/[CH:12]=[CH:13]/[CH:14]=[C:15](\[O:20][CH3:21])/[C:16]([OH:18])=[O:17])=[CH:5]2
Reactant: COC(=O)/C(=C/C=C/c1cc2cc(Cl)c(Cl)cc2[nH]1)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CO/C(=C\C=C\c1cc2cc(Cl)c(Cl)cc2[nH]1)C(=O)O
Temperature: 25 °C
Yield: 99 %

Procedure:
A suspension of methyl (2Z,4E)-5-(5,6-dichloroindol-2-yl)-2-methoxy-2,4-pentadienoate (10 g, 30.7 mmol) and KOH (3.6 g, 64.2 mmol) in EtOH/water {fraction (1/1)} (460 ml) was refluxed for 3 h. The suspension after cooling to RT was poured into water (1.5 l), it was acidified with 2N HCl and extracted with AcOEt (2×1 l). The organic phase was washed with water and dried (MgSO4), then concentrated and the residue taken up with CH2Cl2. Filtration and drying in the oven at 50° produced 9.5 g of pure title compound (30.4 mmol, yield 99.1%), m.p.=249-250° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:19](=O)[C@H:18]2[NH:21][C:22](=O)[C@@H:13]1[CH2:14][CH:15]=[CH:16][CH2:17]2.CC(C[AlH]CC(C)C)C.Cl>C(OCC)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH2:19][C@H:18]2[NH:21][CH2:22][C@@H:13]1[CH2:14][CH:15]=[CH:16][CH2:17]2
Reactant: O=C1N[C@H]2CC=CC[C@@H]1N(Cc1ccc3ccccc3c1)C2=O
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2Cc1ccc2ccccc2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOCC
Product: C1=CC[C@H]2CN[C@@H](C1)CN2Cc1ccc2ccccc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Z-(1S,6S)-7-naphthalen-2-ylmethyl-7,9-diaza-bicyclo[4.2.2]dec-3-ene-8,10-dione (40 mg, 0.1307 mmol) was placed in a μW tube, followed by addition of DiBAl-H (3 mL, 3 mmol, [1M] in THF). The reaction mixture was purged under argon for 20 min, then heated to 130° C. for 900 sec. The reaction mixture was poured in to a 100 mL mixture (1:1) of Rochelle's solution and diethyl ether and stirred vigorously overnight. The reaction mixture was separated and the organic layer was dried with magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield an oil. The oil was treated with 1M HCl in diethyl ether (2 mL) to yield the title compound as a residue.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.[CH2:58]([O:60][C:61](=[O:73])[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([O:68][CH2:69][CH2:70][CH2:71]Cl)[CH:63]=1)[CH3:59].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:82]([OH:89])(=[O:88])/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86]>CN(C)C=O>[C:82]([OH:89])(=[O:88])/[CH:83]=[CH:84]/[C:85]([OH:87])=[O:86].[CH2:58]([O:60][C:61](=[O:73])[C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([O:68][CH2:69][CH2:70][CH2:71][N:48]2[CH2:47][CH2:46][CH:45]([C:43]([C:51]3[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=3)([C:40]3[CH:41]=[CH:42][C:37]([F:36])=[CH:38][CH:39]=3)[OH:44])[CH2:50][CH2:49]2)[CH:63]=1)[CH3:59]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CCOC(=O)c1cccc(OCCCCl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1
Yield: 67 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of α, α-bis(p-fluorophenyl)-4-piperidinemethanol, 2.4 g (0.01 mole) of 3-(3-chloropropoxy)benzoic acid ethyl ester, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of dimethylformamide gave a gum as residue. The gum was converted to the fumaric acid salt and the solid was recrystallized from acetonitrile to yield 4.2 g (67%) of title compound as a fluffy,, white solid, mp 123°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23].C([O:28][CH2:29][CH2:30][O:31][NH2:32])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([NH:32][O:31][CH2:30][CH2:29][OH:28])=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23]
Reactant: CC(C)(C)OCCON
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)c2n(c1=O)CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)NOCCO)c2n(c1=O)CCC2
Temperature: 75 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
Compound 8e (76 mg, 0.23 mmol) was added to a suspension of O-(2-tert-butoxy-ethyl)-hydroxylamine (see, WO05/110410, 47 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), and N-methylmorpholine (0.10 mL, 0.90 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 16 h and concentrated in vacuo. The resulting oil was dissolved in 3 mL of TFA and allowed to stir at RT for 2 h. Then MeOH (3 mL) was added and made basic with potassium carbonate. It was allowed to stir for 30 minutes, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile) to give 4 mg (5%) of Example 8 as a white solid. 1H NMR (400 MHz, MeOD): δ 7.43 (d, 1H, J=8.9 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.43 (t, 1H, J=8.6 Hz), 4.14 (t, 2H, J=7.3 Hz), 3.85 (m, 2H), 3.67 (m, 2H), 3.29 (t. 2H, J=7.6 Hz), 2.09-2.27 (m, 2H), 1.83 (s, 3H). MS (ES) [m+H] calc'd for C18H19FIN3O4, 488. found 488.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: NC(=O)Cc1nc(Cl)nc2ccccc12
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2nc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 50 °C

Procedure:
2-(2-chloro-quinazolin-4-yl)-acetamide (221 mg, 1.0 mmol) is dissolved in 1-methyl-2-pyrrolidinone (2.0 mL) and N-methylpiperazine (555 μL, 5.0 eq.) is added. The mixture is heated 45 min. at 50° C. AcOEt is added and the suspension is filtered to afford 2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3([C:26]#[N:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>ClCCl>[C:1]([N:23]1[CH2:22][CH2:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:15][CH:16]=2)([C:26]#[N:27])[CH2:25][CH2:24]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
Acetyl chloride (27 μl, 0.37 mmol) was added dropwise to a solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile (90 mg, 0.28 mmol) and triethylamine (78 μl, 0.56 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (15 ml) and washed with water (15 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×10 ml). The organics were combined, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:methanol:ammonia (95:5:0.5 by volume) to provide the title compound (28 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 1.82-1.85 (m, 4H), 1.89-2.18 (m, 9H), 2.60-2.63 (m, 4H), 2.69 (t, 2H), 3.00 (t, 1H), 3.50 (t, 1H), 4.03-4.12 (m, 3H), 4.70 (d, 1H), 6.97 (d, 2H), 7.44 (d, 2H). HRMS ESI+ m/z 356.2329 [MH]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:10]=[C:11]2[C:17](=[CH:18][CH:19]=1)[CH:16]1[O:20][CH:12]2[CH2:13][NH:14][CH2:15]1)([O-:8])=[O:7].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][S:2]([N:14]1[CH2:13][CH:12]2[O:20][CH:16]([C:17]3[C:11]2=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:19][CH:18]=3)[CH2:15]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CNCC2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Methanesulfonyl chloride (133 mg, 1.16 mmol) was added to a solution of 4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (200 mg, 0.55 mmol) and potassium carbonate (276 mg, 2.0 mmol) in THF (5 mL). The solution was stirred at 70° C. for 1 h. The reaction was then concentrated and purified with silica gel chromatography (0-100% EtOAc in hexanes) to give 10-Methanesulfonyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene as a light tan solid (150 mg, 54%). MS (m/e) 285 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:10])[NH2:9].CC(C)([O-])C.[K+].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25](=[C:27]([C:33](OCC)=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:26].Cl>CN(C)C=O>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1([CH3:26])[CH:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:33](=[O:34])[NH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[N:10]1
Reactant: N=C(N)c1ccccn1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(=O)NC(c2ccccn2)=NC1(C)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 45 h
Yield: 32 %

Procedure:
Under a nitrogen atmosphere, a pressure tube was charged with a magnetic stirring bar, pyridine-2-carboximidamide hydrochloride (268 mg, 1.70 mmol), N,N-Dimethylformamide (13.2 mL), potassium tert-butoxide (382 mg, 3.41 mmol) and diethyl 2-(1-(2,4-difluorophenyl)ethylidene)malonate (508 mg, 1.70 mmol). The reaction mixture was sealed and stirred at 60° C. for 45 hours. After cooling to room temperature, the reaction mixture was poured into ice water (200 mL) and the resulting emulsion was neutralized (pH=7) using hydrochloric acid (1N). The mixture was extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. N,N-Dimethylformamide was co evaporated using toluene and the resulting yellow oil was purified using silica gel column chromatography with ethyl acetate in heptane in a gradient from 10 to 40%. The desired fractions were concentrated in vacuo yielding ethyl 4-(2,4-difluorophenyl)-4-methyl-6-oxo-2-(pyridin-2-yl)-1,4,5,6-tetrahydropyrimidine-5-carboxylate (203 mg). Under a nitrogen atmosphere, a tube was charged with a stirring bar, ethyl 4-(2,4-difluorophenyl)-4-methyl-6-oxo-2-(pyridin-2-yl)-1,4,5,6-tetrahydropyrimidine-5-carboxylate (137 mg, 0.367 mmol) and phosphorous oxychloride (0.509 mL, 5.48 mmol). The mixture was stirred and heated at reflux for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated to dryness. The obtained residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate (3×10 mL), dried (isolute HM-N) and evaporated to resulting in ethyl 6-chloro-4-(2,4-difluorophenyl)-4-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (154 mg) as a yellow powder which was used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.[Cu]>[C:18]([O:17][C:15]([N:9]1[CH2:14][CH2:13][N:12]([C:2]2[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:11][CH2:10]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: Clc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2Cl)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 2,3-dichloropyridine (10 g, 67.5 mmol, Aldrich), tert-butyl 1-piperazinecarboxylate (12.58 g, 67.5 mmol, Aldrich), copper powder (0.5 g, 7.8 mmol) and K2CO3 (9.33 g, 67.5 mmol) in DMF (100 mL) was stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was dissolved in EtOAc (200 mL). The organic solution was washed with saturated aqueous solution of NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 15% EtOAc/hexane, to give the title compound as an orange oil. MS (ESI, pos. ion) m/z: 298 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[OH:15].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([O:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CCO[C@H]2CCCC[C@H]2O)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CCO[C@H]2CCCC[C@H]2OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A 10-mL round bottom flask under nitrogen atmosphere was charged with cis-2-(3,4-dimethoxyphenethoxy)cyclohexan-1-ol (13) (80 mg, 0.28 mmol), anhydrous dichloromethane (3 mL), and anhydrous pyridine (70 μL, 0.86 mmol). After the reaction mixture was cooled to 0° C., a solution of 4-nitro-benzenesulfonyl chloride (95 mg, 0.43 mmol) in anhydrous dichloromethane (1.5 mL) was added dropwise. The reaction was stirred at 0° C. for 30 minutes, and then at room temperature until total consumption of all starting material 13 (20 h), as revealed by TLC (1:1, v/v EtOAc:hexane). The reaction mixture was diluted with dichloromethane (10 mL) and aqueous H2SO4 (5%, 10 mL). After the aqueous layer was extracted with CH2Cl2 (2×10 mL), the organic layers were combined, washed successively with diluted aqueous H2SO4 (5%, 10 mL) and brine (10 mL), dried (anhydrous MgSO4), and concentrated in vacuo to give a yellow oil. Purification of this crude material by elution through a silica gel plug using a mixture of ethyl acetate-hexanes (1:2, v/v) afforded 14 (95 mg, 72%). Rf 0.71 (EtOAc-hexanes, 1:1, v/v); 1H-NMR (400 MHz, CDCl3) δ 1.21-1.69 (m, 8H), 2.01-2.11 (m, 1H), 2.63 (t, 2H, J 6.9 Hz), 3.36-3.38 (m, 1H), 3.43-3.57 (m, 2H), 3.83 (s, 6H, OCH3), 4.84-4.86 (m, 1H), 6.63-6.69 (m, 2H), 6.75 (d, 1H, J 8.1 Hz), 8.01-8.05 (m, 2H), 8.24-8.28 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 21.19, 21.57, 27.20, 29.00, 35.90, 55.76, 55.87, 69.93, 82.65, 111.07, 112.19, 120.63, 124.06, 128.92, 131.39, 143.45, 147.45, 148.68, 150.33.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[CH:23](OCC)=[O:24]>>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:23]=[O:24])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC=O
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Product: O=CNc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
A solution of 4-(2-aminophenylamino)benzophenone (Compound 101 0.29 g, 1.0 mmol) in ethyl formate (5.0 ml, 63 mmol) was refluxed for 16 hours. The reaction mixture was evaporated in vacuo and dissolved i ethyl acetate. The solution was filtered and evaporated in vacuo. The residue was crystallized on the addition of diethyl ether to afford the pure title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C[O-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([OH:27])=[C:16]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)[CH:17]=1.C(O)C>CO>[Cl:11][C:12]1[CH:13]=[C:14]([CH3:28])[C:15]([OH:27])=[C:16]([C:18](=[N:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH:17]=1
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1cc(Cl)cc(C(=NCCCC(=O)O)c2ccc(Cl)cc2)c1O

Procedure:
4-Aminobutanoic acid (2.2 g; 0.0213 mol), sodium methoxide (1.16 g; 0.0213 mol) and (5-chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methanone (6 g; 0.0213 mol) are introduced into a mixture of 200 ml of ethanol and 400 ml of methanol, and the resulting mixture is then evaporated to dryness. Ethanol (500 ml) is added to the residue and the mixture is then evaporated to dryness. The latter operation is repeated 4 times. The residue is dissolved in 1 liter of water and the pH is acidified to pH 4 by the addition of citric acid. The precipitate is filtered off, washed with water and then dissolved in CH2Cl2. The organic solution is washed with water, dried (MgSO4) and filtered, and the filtrate is evaporated to give an oil, which is crystallised once from petroleum ether and recrystallised twice from AcOEt.