Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1.CC([O-])(C)C.[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]2)=[O:27])=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1n[nH]c2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Cc1nn(C(=O)c2ccc(Cl)cc2)c2ccccc12
Reaction time: 0.42 h

Procedure:
To a cooled solution (ice bath, 0-5° C.) of methyl 2-(1H-indazol-3-yl)acetate (80 mg, 0.42 mmol) in THF (2.5 mL) was added tBuONa (2 M in THF, 252.4 μL, 0.50 mmol), and the mixture was stirred for 25 min at the low temperature. 4-Chlorobenzoyl chloride (88.3 mg, 0.50 mmol) was added and the reaction was aged overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl (provided in a commercial phase separator syringe) and the organic compound was extracted with CH2Cl2, washed with brine and water, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was subjected to flash chromatography (SiO2, ethyl acetate/hexane gradient) to afford the title compound as yellow oil, which permanently crystallized upon drying at high vacuum and storage at −20° C. Yield: 51 mg (37%). C17H13ClN2O3, Mr=328.75; 1H NMR (400 MHz, DMSO-d6) d: 3.65 (s, 3H), 4.16 (s, 2H), 7.50 (td, J=0.8/7.6 Hz, 1H), 7.63-7.66 (m, 2H), 7.71 (td, J=1.0/7.6 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 8.00-8.03 (m, 2H), 8.41 (d, J=8.4 Hz, 1H); LCMS (ESI) tR: 2.80 min (>99%, ELSD), m/z: 329.0 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:36])(=[O:35])[N:15]([C@H:20]([CH2:33][OH:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH2:43]([O:45][P:46](Cl)([O:48][CH2:49][CH3:50])=[O:47])[CH3:44].[H-].[Na+]>C(OP(OCC)(OCC)=O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14](=[O:36])(=[O:35])[N:15]([C@H:20]([CH2:33][O:34][P:46]([O:48][CH2:49][CH3:50])([O:45][CH2:43][CH3:44])=[O:47])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)OC(C)(C)C)N(CC(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.00 g (3.7 mmol) (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl ]-phenyl}-carbamic acid tert-butyl ester (VII) (example 1, step D) is dissolved in 0.63 mL triethylphosphate and 10 mL THF at 0° C. under inert argon atmosphere. 0.63 mL (4.44 mmol) diethylchlorophosphate is added and then 0.25 g (6.2 mmol), NaH 60% in oil is added in portionwise. The mixture is allowed to warm to room temperature and left to stir for 2 h (LC-MS showed completion after 1 h). To the solution is added 2 0 mL of Amberlite XAD-2 resin and the slurry thoroughly mixed and added to 200 mL ice water. After stirring for 15 min. the resin suspension is filtered and the resin washed several times with distilled water (500 mL). The desired product is desorbed from the resin with acetone (5×50 mL), EtOAc (5×50 mL), the organic phase is then dried over Na2SO4. After evaporation of the solvent 2.66 g (89%) of clear oil is obtained. The crude product contains a fraction with two diethyl phosphates and is used as is in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[C:4]([CH3:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=3)=[O:29])=[CH:3][C:4]=2[CH3:19])[CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(N)ccc1Oc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1cc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)ccc1Oc1ccnc(N)c1[N+](=O)[O-]
Yield: 143.4 %

Procedure:
Method H3 was used with 4-(4-amino-2-methylphenoxy)-3-nitropyridin-2-amine (0.22 g, 0.991 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.16 g, 0.709 mmol) to afford the title compound (0.49 g, 100%). 1H NMR (250 MHz, 6, ppm, DMSO-d6): 2.10 (s, 3H), 5.81 (d, 1H, J=5.7 Hz), 7.08 (d, 1H, J=8.7 Hz), 7.14 (s, 2H), 7.37 (dd, 1H, Ja=8.8 Hz, Jb=2.6 Hz), 7.49 (d, 1H, J=2.4 Hz), 7.58-7.66 (m, 2H), 7.96 (d, 1H, J=5.7 Hz), 8.12 (d, 1H, J=2.1 Hz), 8.89 (s, 1H), 9.16 (s, 1H). m/z 482.1 [(M+H)+ calcd. for C20H15ClF3N5O4 481.1].
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>CC(O)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[N:3]=[C:2]2[NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26])[CH2:14][CH3:15]
Reactant: CCCOc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Reactant: NC(=O)c1ccccc1N
Solvent: CC(C)O
Product: CCCOc1ccc2nc(-c3cccnc3)nc(Nc3ccccc3C(N)=O)c2c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
(This method is representative of method G1, G2, and G3. These three methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature) A mixture of 4-chloro-6-propoxy-2-(pyridin-3-yl)quinazoline (90 mg, 0.3 mmol) and 2-aminobenzamide (52 mg, 0.4 mmol) in i-PrOH (5 mL) was stirred at 85° C. for 18 h. The yellow precipitate was collected and washed with i-PrOH (10 mL). The solid was suspended in water (10 mL) and NH3—H2O (1 mL) was added. After filtration the solid was dried in vacuo to afford 31.0 mg of vi-a as a white solid (30.8%). LCMS m/z=400.1 (M+1) (Method B) (retention time=1.96 min). 1H-NMR (400 MHz, DMSO-d6): δ 9.59 (d, J=2.0 Hz, 1H), 9.58 (d, J=7.6 Hz, 1H), 8.69-8.74 (m, 2H), 8.48 (s, 1H), 7.97 (d, J=6.8 Hz, 2H), 7.90 (d, J=8.8 Hz 1H), 7.74 (t, J=7.6 Hz, 1H), 7.56-7.61 (m, 3H), 7.20 (t, J=7.2 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 1.86 (dd, J=14.0, 6.8 Hz, 2H), 1.07 (t, J=7.2 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)C.[Si:10]([O:17][C@@H:18]([CH3:51])[CH2:19][CH2:20][CH2:21][C:22](=[O:50])/[CH:23]=[CH:24]/[C@H:25]1[C@H:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:28][C@@H:27]([Cl:37])[C@@H:26]1[CH2:38][CH2:39][CH2:40][C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>C1COCC1>[Si:10]([O:17][C@@H:18]([CH3:51])[CH2:19][CH2:20][CH2:21][C@H:22]([OH:50])/[CH:23]=[CH:24]/[C@H:25]1[C@H:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:28][C@@H:27]([Cl:37])[C@@H:26]1[CH2:38][CH2:39][CH2:40][C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/[C@@H](O)CCC[C@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: -85 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Lithium aluminum hydride (7.5 mL of a 1.0M solution in THF, 7.5 mmol) was added to an oven-dried 200 mL flask. A freshly prepared solution of absolute ethanol (11.9 mL of a 1.0M solution in THF, 7.50 mmol) was added dropwise at 23° C. After 15 min a solution of (S)-(−)-1,1′-binaphthol (2.18 g, 7.62 mmol) in THF (10 mL) was added dropwise. The milky-white solution was cooled to −85° C. and a solution of the enone 14 (1.60 g, 2.50 mmol) in THF (9 mL) was added over a 5-10 min period. The reaction solution was stirred for 1 h and then warmed to −78° C. and allowed to stir an additional 3 h. The reaction was then quenched by careful addition of MeOH (3.1 mL). The reaction was then allowed to warm to room temperature and was extracted with EtOAc (2×). The combined organic portions were washed with 1N HCl, saturated aqueous NaHCO3, and brine. The organic portion was then dried over anhydrous MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 6:1 hex/EtOAc) afforded 1.20 g (75%) of (S)-alcohol 15.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]1[C:17]([O:19]CC)=O)=[N+]=[N-].C(=O)([O-])[O-].[K+].[K+]>CCO.C(Cl)Cl.Cl.[Pd]>[O:19]=[C:17]1[NH:1][CH2:4][CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]12
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CCCN=[N+]=[N-])c1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc2n(c1)CCCNC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of diethyl 1-(3-azidopropyl)-1H-pyrrole-2,4-dicarboxylate Intermediate 7 (8 g, 27.2 mmol) in EtOH (800 mL) was added 10% Pd/C (2 g). The reaction was stirred at rt under a 30 psi H2 atmosphere for 2 h then filtered. To the filtrate was added potassium carbonate (4 g, 28.9 mmol). The reaction was then refluxed overnight. All the solids were then removed by filtration and the filtrate was then concentrated to give a solid which was dissolved in DCM (200 mL) and 1N aqueous HCl. After separation, the aqueous layer was extracted with DCM (2×150 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give ethyl 1-oxo-2,3,4,5-tetrahydro-1H-pyrrolo[1,2-a][1,4]diazepine-8-carboxylate (4 g, 66%). 1H NMR (DMSO-d6, 300 MHz) δ7.88 (s, 1 H), 7.61 (s, 1 H), 6.84 (s, 1 H), 4.19 (m, 4 H), 3.09 (m, 2 H), 1.99 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@H:6]2[C@H:8]3[C:18](=[CH:19][CH2:20][C@:4]2([CH3:5])[C:3]1=[O:22])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3.[C-]#[C-].[Li+].[Li+].[CH3:27][C:28](C)=O>C1COCC1>[C:27]([C@:3]1([OH:22])[C@@H:2]([CH3:1])[CH2:7][C@H:6]2[C@H:8]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C@:16]1([CH3:17])[C:11](=[CH:12][C:13](=[O:21])[CH:14]=[CH:15]1)[CH2:10][CH2:9]3)#[CH:28]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Reactant: CC(C)=O
Agent: [C-]#[C-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C#C[C@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Reaction time: 0.5 h

Procedure:
16β-Methylandrosta-1,4,9(11)-triene-3,17-dione (IB, U.S. Pat. No. 3,010,958, 20 g) is added in THF (60 ml) to the lithium acetylide at -40°. When the reaction is complete, acetone (24 ml) is added. The mixture is warmed while bubbling nitrogen thru the slurry to remove excess acetylene. Water (25 ml) is slowly added. Water (105 ml) is then added more quickly creating two phases which are separated. The aqueous phase is washed with THF (50 ml); the organic phases (pH is 9) are combined, washed with aqueous sulfuric acid and concentrated to 350 ml. Heptane (200 ml) is added, the mixture heated to 80° and held for 30 min. The mixture is cooled slowly to 30° and then to 18° for one hr. The mixture is filtered, the solid washed with heptane (20 ml) and then dried under reduced pressure with heat to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])/[C:8]([O:10][CH3:11])=[O:9])[N:6]=1.C(N(CC)C(C)C)(C)C.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[C:46]([N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:12]/[O:13][C:14]([CH3:15])([CH3:16])[C:17](=[O:19])[CH:70]2[CH2:69][NH:68][CH2:67][CH2:66][N:65]2[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)/[C:8]([O:10][CH3:11])=[O:9])[N:6]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reactant: COC(=O)/C(=N\OC(C)(C)C(=O)O)c1csc(N)n1
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C(=N\OC(C)(C)C(=O)C1CNCCN1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(N)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-amino-α-[(1-carboxy-1-methylethoxy)imino]-4-thiazoleacetic acid, methyl ester (3.16 g, 11.0 mmol) in dimethylformamide (44 ml) and N,N-diisopropylethylamine (2.11 ml, 12.1 mmol) at -10° C. was added diphenylchlorophosphate (2.51 ml, 12.1 mmol). After one hour at -10° C., a solution of N-tritylpiperazine (3.87 g, 11.0 mmol correcting for 7% by weight triethylamine) in tetrahydrofuran (20 ml) and triethylamine (1.54 ml, 11.0 mmol) was added over 15 minutes. The reaction was stirred for an additional 15 minutes at -10° C. and for 2 hours at 0° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[N:8]=[CH:7]2)([O-])=O>CO.CCOC(C)=O.[Pd]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccn2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reaction time: 1.75 h

Procedure:
To 5-nitro-1-pyridin-2-ylmethyl-1H-indazole (Step 1) (671 mg, 2.63 mmol) in MeOH (15 mL) and EtOAc (5 mL) at RT was added a slurry of 10% Pd/C (150 mg) in MeOH (5 mL). The resulting slurry was stirred under a balloon of H2 for 1.75 h, filtered through Celite®, and rinsed with MeOH and EtOAc. Concentration of the filtrate gave 1-pyridin-2-ylmethyl-1H-indazol-5-ylamine.
Reaction SMILES: [F:1][C:2]([F:21])=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6](NC(OC(C)(C)C)=O)[CH2:5][CH2:4]1.Cl>ClCCl.O1CCOCC1>[F:21][C:2]([F:1])=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NN1CCC(=C(F)F)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)=C1CCNc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 104.1 %

Procedure:
0.11 g of tert-butyl 4-difluoromethylene-3,4-dihydro-2H-quinoline-1-carbamate in 10 ml of dichloromethane is introduced into a round-bottomed flask equipped with a magnetic stirrer. 6 ml of a 4N solution of hydrochloric acid in dioxane are added. After stirring at ambient temperature for 6 h, the reaction medium is concentrated under vacuum. 0.07 g of 4-difluoromethylene-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(F)cc2Cl)=N1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2-chloro-4-fluoro-benzylbromide (89.2 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (73.0 mg, 48.7%).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][NH2:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(#N)CO>O>[CH2:5]1[CH2:6][CH2:7][N:1]([CH2:8][C:9]#[N:10])[CH2:2][CH2:3][CH2:4]1
Reactant: NCCN1CCCCCC1
Agent: N#CCO
Solvent: O
Product: N#CCN1CCCCCC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Azepane (289) (4.9 mL, 43.8 mmol) was added dropwise to a stirred aqueous solution of glycolonitrile (55%, 5.0 g, 48.2 mmol) at 5° C. and the solution was stirred at 70° C. for 30 min. The solution was cooled, diluted with water (20 mL), washed with Et2O (3×50 mL). The organic fraction was dried and the solvent evaporated to give nitrile 290 (5.58 g, 92%) as a colourless oil: 1H NMR δ 3.56 (s, 2H, CH2CN), 2.71 (br dd, J=5.8, 5.5 Hz, 4H, 2×CH2N), 1.67-1.73 (m, 4H, 2×CH2), 1.59-1.64 (m, 4H, 2×CH2).
Reaction SMILES: [Cl:1][C:2]1C=[CH:6][CH:5]=[CH:4][C:3]=1C.[C:9]([OH:12])(=[O:11])[CH3:10]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:10]=1[C:9]([OH:12])=[O:11]
Reactant: CC(=O)O
Reactant: Cc1ccccc1Cl
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccccc1Cl
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Analogously to Example 1, 300 g of o-chlorotoluene was oxidized in the presence of 100 g of acetic acid, 3 g of cobalt acetate tetrahydrate and 1.5 g of sodium bromide at a pressure of 25 bar, a temperature of 110°-130° C., and a gas exhaust rate of 3 1/min. After the oxidation had ended, 450 g of 50% acetic acid was added, the mixture was cooled to 25° C. and filtered, and the filter cake was washed with 750 g of 50% acetic acid, the mother liquor (314.5 g) and washing filtrates (693.5 g) being recovered separately. The dried filter cake yielded 318.5 g of o-chlorobenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:23][C:24]3[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:33])=[N:19][CH:20]=2)[N:15]([CH3:34])[C:14]1=[O:35].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:33])[C:24]=1[NH:23][C:18]1[N:17]=[C:16]2[N:15]([CH3:34])[C:14](=[O:35])[N:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[CH2:22][C:21]2=[CH:20][N:19]=1
Reactant: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3N(C)C2=O)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(N2Cc3cnc(Nc4c(C)cccc4N)nc3N(C)C2=O)c1Cl
Temperature: 70 °C
Reaction time: 6 h
Yield: 9.9 %

Procedure:
A mixture of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-7-(2-methyl-6-nitrophenylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (290 mg, 0.56 mmol) in ethanol (10 mL) and water (2 mL) was stirred at 70° C. for 20 mins before iron powder (320 mg, 5.60 mmol) and ammonium chloride (250 mg, 2.79 mmol) were added. The reaction mixture was stirred at 70° C. for another 6 h. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated. The residue was dissolved by ethyl acetate (30 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Prep-HPLC to give the title compound (27 mg, 10%) as a white solid. MS (ES+) C22H22Cl2N6O3 requires: 488, 490. found: 489, 491 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ ppm 7.89 (s, 1H), 7.04 (t, 1H, J=8.0 Hz), 6.69 (d, 2H, J=7.5 Hz), 6.60 (s, 1H), 4.53 (s, 2H), 3.94 (s, 6H), 3.34 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: C1(=O)OC(=O)C=C1.[CH2:8]([C:10]1([CH3:21])[CH:15]([CH3:16])[CH:14]([NH2:17])[CH2:13][C:12]([CH2:19][CH3:20])([CH3:18])[NH:11]1)[CH3:9].[C:22]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12>O1CCOCC1>[CH2:8]([C:10]1([CH3:21])[CH:15]([CH3:16])[CH:14]([NH:17][C:22](=[O:32])[C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([OH:27])=[O:26])[CH2:13][C:12]([CH2:19][CH3:20])([CH3:18])[NH:11]1)[CH3:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CCC1(C)CC(N)C(C)C(C)(CC)N1
Agent: O=C1C=CC(=O)O1
Solvent: C1COCCO1
Product: CCC1(C)CC(NC(=O)c2ccccc2C(=O)O)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
49.0 g of maleic anhydride in 300 ml of dioxane are heated to 80° C. At this temperature 99.2 g of 2,6-diethyl-2,3,6-trimethyl-4-aminopiperidine are added dropwise in the course of 30 minutes. After a short time a light brown precipitate is formed. The reaction is continued for 1 hour at reflux temperature. The reaction mixture is then cooled to room temperature, and the precipitate is filtered off. The resultant residue is dissolved in 500 ml of warm water. A brownish solution is formed which is discoloured with active carbon, and then evaporated to dryness under vacuo. The solid residue is suspended in about 200 ml of warm ethanol, the suspension is cooled to room temperature, filtered and dried. 2,6-Diethyl-2,3,6-trimethyl-4-β-carboxy-acrylamidopiperidine (compound no. 42) is obtained: m.p. >250° C. If, instead of 49.0 g of maleic anhydride an equivalent amount of phthalic anhydride is used and otherwise the procedure described above if followed, 2,6-diethyl-2,3,6-trimethyl-4-o-carboxybenzamidopiperidine (compound no. 43 ) is obtained; m.p. 196°-197° C.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[N:17]=[C:18]([CH3:22])[O:19][C:20](=[O:21])[C:15]=3[C:14]3[CH:13]=[C:12]([F:23])[CH:11]=[CH:10][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[BH4-].[Na+].O>O1CCCC1>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:16]([NH:17][CH2:18][CH3:22])=[C:15]([C:20]([OH:21])=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:23])[CH:13]=3)[N:8]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc2c(-c3ccc(-c4ccccc4)cc3)nc3ccc(F)cc3c2c(=O)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(F)cc2c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution of 4.0 g of 5-[1,1'-biphenyl]-4-yl-9-fluoro-3-methyl-1H-[1,3]oxazino[4,5-c] quinoline-1-one in 200 ml of tetrahydrofuran at 0° C. was added 0.91 g of sodium borohydride. The solution was stirred at 0° C. for 1 hour, then allowed to warm to 20° C. and stirred for 12 hours. A 50 ml portion of water was added and the foaming solution stirred for 10 minutes. The volatiles were removed in vacuo, then 40 ml of 0.5N sodium hydroxide was added and the solution extracted with two 100 ml portions of dichloromethane. The extracts were combined, extracted with 100 ml of water containing 5 ml of 1N sodium hydroxide and the aqueous layer from this extraction extracted with 100 ml of dichloromethane. The aqueous layers were combined, filtered through celite and acidified to pH 4 with 3 % aqueous hydrochloric acid. The resulting solid was collected, washed with water and dried, giving 2.8 g of the desired product as a yellow solid, mp 180°-182° C. (dec.)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:3]=1.[CH3:17][O:18][C:19]([CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)=[O:20]>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[NH:8][C:4]1[CH:3]=[C:2]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][C:19]([O:18][CH3:17])=[O:20])=[CH:24][CH:25]=2)[N:7]=[CH:6][N:5]=1
Reactant: COC(=O)COc1ccc(N)cc1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Product: COC(=O)COc1ccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)cc1
Yield: 26 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-chloro-4'-fluoroanilino)pyrimidine (0.258 g) was reacted with 4-methoxycarbonylmethoxyaniline (0.195 g). The reaction product was chromatographed on silica and precipitated from a mixture of methylene chloride, methanol and hexane to give 4-(3'-chloro-4'-fluoroanilino)-6-(4'-methoxycarbonylmethoxyanilino)pyrimidine in 26% yield, m.p. 191°-193° C.