Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]2[CH2:30][NH:29][CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:17][CH:16]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](O)(=O)C.C=O>CO>[CH2:1]([C:8]1[C:9]2[CH2:30][N:29]([CH3:31])[CH2:28][CH2:27][C:10]=2[N:11]=[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[C:22]3[CH3:26])=[CH:19][CH:20]=2)[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CNCC3)cc1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(Cc4ccccc4)n2)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
4-benzyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (75 mg, 0.19 mmol, Example 41a) was dissolved in methanol (2 mL). Acetic acid (10.83 μL, 0.19 mmol) was added followed by formaldehyde (0.014 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 15 minutes and MP-CNBH3 was added. The reaction was stirred for 1 h, the MP-CNBH3 was filtered off and the solvent was evaporated under reduced pressure. The crude was dissolved in methanol, filtered and purified by preparative HPLC yielding 4-benzyl-6-methyl-N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (23.00 mg, 27%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1([C:13](OC)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.Cl.[OH-].[Na+]>C1COCC1.O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][CH2:6][C:8]1([CH2:13][OH:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1(C(=O)NCCC(C)C)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCNCC1(CO)CCCC1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 1-[N-(3-methylbutyl)-carbamoyl]-cyclopentanecarboxylate (900 mg, 3.7 mmol) in THF at rt was added BH3/THF complex ) 7.4 mL, 7.4 mmol) and stirred at 75° C. for 5 hours. To this reaction mixture was added 6N HCl (10 mL) and the mixture was further stirred for 30 min before the solution was neutralized by 1N NaOH. The solution was diluted with water and extracted with EtOAc. The combined extracts were dried over magnesium sulfate, and concentrated to a crude oil (700 mg, 95%). MS [M+H]+200.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:35]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:34]=1[C:59]([O-])=[O:60])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([NH+](CC)CC)C.CCN(C(C)C)C(C)C.[C:78]([NH:81][NH2:82])(=[O:80])[CH3:79]>CN(C=O)C>[C:78]([NH:81][NH:82][C:59]([C:34]1[N:35]([C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=2)[C:36]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[C:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:33]=1[O:32][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:60])(=[O:80])[CH3:79]
Reactant: CC(=O)NN
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)[O-])n1-c1ccc(OC)cc1
Agent: CC[NH+](CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)NNC(C)=O)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
HATU (739 mg, 1.94 mmol) was added to a solution of triethylammonium 3,4-bis(benzyloxy)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (5) (325 mg, 0.65 mmol), DIPEA (566 μL, 3.24 mmol) and acetohydrazide (53 mg, 0.71 mmol) in DMF (5 mL) at 0° C. The mixture was stirred for 30 min and allowed to warm to RT. The reaction was partitioned between water (10 mL) and Et2O (30 mL) and NH4OAc (aq.) (20 mL) was added, the organic layer was separated and washed with sat. NaHCO3 (aq.) (20 mL), brine (20 mL), dried (MgSO4), filtered and solvents removed in vacuo. The product was purified by silica gel chromatography (40 g, 0-80% EtOAc in isohexane) to afford ethyl 5-(2-acetylhydrazinecarbonyl)-3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (31) (196 mg, 100%) as a colourless oil: m/z 558 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Product: CCOC(=O)C1CCCN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2,4-dichloropyrimidine (Alfa Aesar, 10 g, 65.8 mmol) and TEA (Sigma-Aldrich, 9.15 mL, 65.8 mmol) in EtOH (68.5 mL) at 0° C. was added ethyl piperidine-3-carboxylate (Sigma-Aldrich, 10.64 mL, 65.8 mmol) in EtOH (13.70 mL). The reaction was then allowed to warm to room temperature while stirring. After 1 hour, the reaction was concentrated and the residue was purified by chromatography through a 340 g silica gel column, eluting with 10% to 80% EtOAc/hexanes, to provide ethyl 1-(2-chloropyrimidin-4-yl)piperidine-3-carboxylate as a colorless oil in 80% yield. 1H NMR (300 MHz, CDCl3) δ ppm 0.94 (t, J=6.94 Hz, 3H) 1.26 (d, J=9.35 Hz, 1H) 1.38-1.62 (m, 2H) 1.66-1.85 (m, 1H) 2.26 (m, 1H) 2.90-3.20 (m, 2H) 3.64 (m, 1H) 3.69-4.09 (m, 3H) 6.23 (d, J=5.85 Hz, 1H) 7.68 (d, J=5.99 Hz, 1H); ESI-MS M+H 270.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](=[O:11])O[CH:10]=1)=[O:4].[NH2:12][CH2:13][CH2:14][NH2:15]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8](=[O:11])[N:12]([CH2:13][CH2:14][NH2:15])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(=O)oc1
Reactant: NCCN
Solvent: CCO
Product: COC(=O)c1ccc(=O)n(CCN)c1
Reaction time: 4 h

Procedure:
To a 500 ml 3-necked flask fitted with a magnetic stirrer bar, addition funnel, nitrogen inlet, and containing 2-oxo-2H-pyran-5-carboxylic acid methyl ester (coumalic acid methyl ester) (10.0 g, 65.0 mmol) and absolute ethanol 160 ml) was added, over 3-5 minutes at room temperature, a solution consisting of 1,2-diaminoethane (17.4 ml, 260 mmol) and abs. ethanol (50 ml). Stirring was continued for 4 hours at which time the suspension was filtered. Concentration of the flitrate gave 1-(2-aminoethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylic acid methyl ester which was used without purification.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[CH2:21]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[C:26]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:25]=1[O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:22].O>C1COCC1>[Si:33]([O:32][C:26]1[C:27](/[CH:28]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:30][CH:31]=[C:24]([O:23][CH2:21][CH3:22])[C:25]=1[O:40][Si:41]([C:44]([CH3:45])([CH3:47])[CH3:46])([CH3:42])[CH3:43])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.6 %

Procedure:
n-Butyl lithium (0.85 mL, 1.36 mmol, 1.6 M in hexanes) was added dropwise over 10 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.58 g, 1.12 mmol) in THF (7 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70 C and a solution of 35 (0.47 g, 1.14 mmol) in THF (3 mL) was added and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and concentrated in vacuo to give crude product (0.67 g). Purification by column chromatography (SiO2 2:98 EtOAc:cyclohexane+1% Et3N) gave 36 (0.21 g, 34%) as an 89:11 mixture of Z:E isomers.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[CH:6][C:5]=1[Cl:12].[OH-].[Na+]>CO>[Cl:12][C:5]1[CH:6]=[C:7]([CH3:11])[C:8]([F:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(F)c(C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Cl)c(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 2-chloro-5-fluoro-4-methyl-benzoic acid methyl ester (Example 252a, 57.77 g) in methanol (400 mL) was treated with sodium hydroxide 2 M solution (285 mL) under nitrogen. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was extracted with diethyl ether (discarded) and the aqueous layer diluted with 2 M hydrochloric acid (250 mL). The reaction mixture was extracted with ethyl acetate (500 mL). The combined organics were dried (MgSO4), filtered and evaporated to afford the subtitle compound (51.6 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5](=[O:13])C(=O)[NH:7]2)[CH3:2].C(C1C=CC(C(O)=[O:21])=C(N)C=1)C>>[CH2:1]([C:3]1[C:4]([C:5]([OH:13])=[O:21])=[C:8]([NH2:7])[CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)O)c(N)c1
Reactant: CCc1cccc2c1C(=O)C(=O)N2
Product: CCc1cccc(N)c1C(=O)O

Procedure:
Oxidation of 9.6 gm of 4-ethyl isatin according to the method described in (iii), above, gave 7.3 gm of the title compound: mp. 99°-104° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:34][O:35][C:36]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:37]=1[CH2:38][N:39]1[C:42](=[O:43])[C@@H:41]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:40]1[CH:55]=O>C1COCC1>[CH3:34][O:35][C:36]1[CH:60]=[C:59]([O:61][CH3:62])[CH:58]=[CH:57][C:37]=1[CH2:38][N:39]1[C:42](=[O:43])[C@@H:41]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:40]1/[CH:55]=[CH:2]/[O:3][CH3:4]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2C=O)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO/C=C/[C@@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (10.34 g, 30.2 mmol) in THF (100 mL) at −78° C. was added KHMDS (in toluene) (66.3 ml, 33.1 mmol) slowly. After stirring for 30 min, the above prepared ylide soln was added to a soln of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-formyl-4-oxoazetidin-3-yl)carbamate (3 g, 7.53 mmol) in THF (38 ml) at −78° C. After 3 h, the reaction mixture was quenched with saturated NaHCO3 (aq, 60 mL), and it was stirred overnight. The mixture was diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (2×), and the combined organic layers were washed with brine, dried with Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-60%) to afford the title compound (1.6 g, 49%) along with the trans-isomer (0.8 g, 25%). LCMS: Rt=0.91 min, m/z=427.0 (M+1). Method 2m_acidic.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1cc(-c2cncc(CN(c3ccc(C)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-methylphenyl)amino]piperidine (581 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=O)[CH:6]=[CH:5][CH:4]=1.[CH3:13][NH:14][CH3:15]>>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([N:14]([CH3:15])[CH3:13])=[O:11])[CH:6]=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COC(=O)c1cccc(CO)n1
Product: CN(C)C(=O)c1cccc(CO)n1
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
Methyl 6-(hydroxymethyl)picolinate (0.598 mmol, 100 mg) was suspended in dimethylamine (2M in MeOH) (2.99 mmol, 1496 μl) and heated to 150° C. for 20 minutes in a microwave. Heating was repeated for a further 20 minutes then further dimethylamine (2M in MeOH) (2.99 mmol, 1496 μl) added and heating repeated again for 20 minutes. Solvent was evaporated under reduced pressure to yield 6-(hydroxymethyl)-N,N-dimethylpicolinamide (103% yield) as a clear oil. 1H NMR (CD3OD) δ: 7.95 (d, 1H), 7.82 (t, 1H), 7.50 (d, 1H), 4.75 (s, 2H), 2.73 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([F:13])[CH:5]=1.C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:18])=[O:9])=[C:6]([F:13])[CH:5]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(C(=O)O)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)Cl)c(F)c1

Procedure:
2-Fluoro-terephthalic acid 4-methyl ester (J. Med. Chem., 52(19), 5950-5966; 2009) (500 mg, 2.25 mmol) was suspended in DCM (10 ml). Then oxalyl chloride (5.08 ml, 58.0 mmol) and a drop of DMF were added. The resulting mixture was refluxed for 14 hrs. The solvents were removed in vacuo, and the resulting crude Intermediate 33 was used in the next step without purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:22][CH3:23].[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O>[CH3:23][O:22][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][NH:28][CH2:27][CH2:26][O:25][CH3:24])[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCCN
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Solvent: O
Product: COCCNCCOc1cc2ncnc(Oc3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (1.1 g, 2.9 mmol), (prepared as described for the starting material in Example 22), in 2-methoxyethylamine (8 ml) was stirred at ambient temperature for 4 hours. The mixture was diluted with water and extracted with methylene chloride (5×25 ml). The combined extracts were washed with brine and passed through phase separating paper. The solvent was removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1) to give 6-methoxy-4-phenoxy-7-(2-(2-methoxyethylamino)ethoxy)quinazoline (760 mg, 70%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:39])=[CH:36][C:37]=2[CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:37]1[CH:36]=[C:35]([CH3:39])[N:34]=[CH:33][C:32]=1[C:28]1[CH:27]=[C:26]([C:24]2[CH2:23][C:22](=[O:40])[NH:21][C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=3[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C)cc3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cnc(C)cc3C)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M232) (340 mg, 0.595 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (148 mg, 55%).
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccncc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g, 0.0052 mol) was suspended in 20 ml of toluene. Isonicotinoyl chloride hydrochloride (0.93 g, 0.0052 mol) was added and then a solution of sodium hydroxide (1.25 g of 50% aqueous NaOH) in 5 ml of water was added dropwise. After stirring at 23° C. for 2 hours, the solids were removed by filtration, washed with water and dried in air. The crude product was chromatographed on silica gel using 5% methanol/methylene chloride as eluant to afford pure N'-t-butyl-N-benzoyl-N'-isonicotinoylhydrazine: m.p. >210° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:23]([Cl:22])=[O:25])[CH:13]=[CH:14][CH:15]=1
Reactant: COc1cccc(Nc2ccccc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(N(C(=O)Cl)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a cooled solution of 3-methoxy-N-phenylaniline (100.0 mg, 0.502 mmol) and pyridine (0.102 mL, 1.267 mmol) in DCM (500 mL) was added triphosgene (120.0 mg, 0.406 mmol). The solution was allowed to warm up to room temperature and stirred overnight. The organic solvent was evaporated. The residue was dissolved in ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated to provide the title compound (105.0 mg). LCMS m/z=261.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 6.90-7.31 (m, 3H), 7.32-7.52 (m, 4H), 7.52-7.70 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][N:13]([CH3:25])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[H][H]>C(O)C.[Ni]>[CH3:1][S:2]([NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][N:13]([CH3:25])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(N)cc1
Yield: 72.2 %

Procedure:
A solution of 1-(4-methanesulphonamidophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]ethane (0.9 g) in ethanol (100 ml) was stirred for 16 hours at room temperature under three atmospheres of hydrogen in the presence of Raney Nickel ("Nicat 102"--Trade Mark). The reaction mixture was filtered and evaporated to dryness. The resultant solid was crystallised from toluene to give the title compound as yellow crystals, (0.6 g), m.p. 155°-157°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.C([O:24][B:25](OCC)[O:26]CC)C.Cl>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:25]([OH:26])[OH:24])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCOB(OCC)OCC
Reactant: CCCCCCCCOc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Temperature: -78 °C
Yield: 55.8 %

Procedure:
1-bromo-4-(octyloxy)benzene (14.64 g, 51.3 mmol) was dissolved in dry tetrahydrofuran in nitrogen atmosphere and cooled to −78° C. Butyllithium (50 ml, 80.0 mmol) was then added drop wise and the reaction mixture was let to room temperature. After an hour the mixture was once again cooled to −78° C. and triethylborate (23.6 g, 0.162 mol) was added drop wise. The reaction mixture was stirred over night at room temperature, acidified with 2M HCl, and the organic phase was recovered. It was washed once with water and three times with 1M sodium hydroxide to form a white soapy solid. The combined alkaline phases were acidified with 2M HCl and extracted with ether three times. The combined ether phases were washed with water and dried over magnesium sulphate. The product precipitated in dichloromethane from the reduced ether phase to yield 4-(octyloxy)phenylboronic acid (7.15 g, 28.6 mmol) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a mixture of N-methylpiperizine (1.00 g, 10 mmol) and Et3N (2.1 mL, 15 mmol) in CH2Cl2 (50 mL) at rt was added 4-bromobenzoyl chloride (2.195 g, 10 mmol) in one portion. The reaction was heated to reflux briefly and cooled. The resulting mixture was stirred O/N at rt. The reaction was quenched with H2O (30 mL) and sat. NaHCO3 (10 mL), separated and dried (Na2SO4). Evaporation of solvents afforded the title compound as a pale yellowish white solid (2.69 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.70-3.20 (m, 4H), 2.40-2.15 (m, 7H; s, 3H at 2.18 ppm and m, 4H overlapping); MS ESI 283.0 [M+H]+, calcd. for [C12H15BrN2O+H]+ 283.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Br
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)NC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-methylbenzene-1-sulfonyl chloride (1.50 g) in dichloromethane (10 ml) at 0° C. was added tert-butylamine (1.5 ml). The reaction mixture was allowed to warm to and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with 1N HCl and with sat. aq. NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated to give 1.20 g 4-bromo-N-tert-butyl-3-methylbenzenesulfonamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cnn(-c4ccc(F)cc4)c3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1ccc(-n2cc(-c3ccc([C@H]4CNCCO4)cc3)cn2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-tert-Butyl 2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)morpholine-4-carboxylate (45 mg, 0.106 mmol) was dissolved in dioxane (0.2 ml) and a solution of HCl in dioxane (4M, 0.4 ml, 1.59 mmol) was added. The reaction mixture was stirred at 60° C. overnight. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)morpholine hydrochloride (38 mg, 99%) as a white solid. MS (ISP): 324.2 ([M+H]+).