Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[C:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:3]([O:19][CH2:18][C:17]([F:21])([F:20])[F:16])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)C(Cc1ccc(O)cc1)=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(O)cc1)OCC(F)(F)F
Reaction time: 0.25 h

Procedure:
A solution of methyl 2-diazo-3-(4-hydroxyphenyl)propanoate (3.00 g) in 2,2,2-trifluoroethanol (10 mL) was slowly added, over 15 minutes, to a stirred mixture of rhodium (II) acetate dinner (0.064 g) and 2,2,2-trifluoroethanol (5 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at temperature for 15 minutes, then heated at reflux for 4 hours, cooled and evaporated. The residue was chromatographed on silica gel with 4% ethyl acetate in dichloromethane to afford the title compound, a gum, which was used without further purification.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16]>O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCC(N)CO
Solvent: C1CCOC1
Product: CCC(CO)NC(=O)c1ccccc1N
Yield: 82.7 %

Procedure:
10.0 g (61 mmol) of isatoic anhydride and 11 g (123.6 mmol) of 2-amino-1-butanol in 200 ml of tetrahydrofuran were heated under reflux for 8 hours. The tetrahydrofuran was then removed under reduced pressure and the resulting residue was distributed between 2M aqueous sodium hydroxide solution and ethyl acetate. The ethyl acetate phase was dried and concentrated under reduced pressure. 10.5 g (82%) of the product were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl.CN1CCCC1=O>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([NH2:18])[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][O:19]1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
Under nitrogen, the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (500 mg, 2.04 mmol) obtained in Example 411 was suspended in dichloromethane (10 ml), and 3,4-dihydro-2H-pyran (205 μl, 2.24 mmol) and pyridinium p-toluenesulfonate (51 mg, 0.204 mmol) were added thereto, followed by adding thereto p-toluenesulfonic acid monohydrate (387 mg, 2.04 mmol). N-methyl-2-pyrrolidinone (10 ml) was added thereto to effect dissolution, and the resulting solution was stirred as follows: at room temperature for 17 hours; at 60° C. for 3.5 hours; and then at 80° C. for 10 hours. The reaction solution was cooled to room temperature and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform (twice). The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluents: chloroform/methanol=20/1 and chloroform/methanol/aqueous ammonia=10/0.8/0.1) to obtain cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexanamine (602 mg, yield 89.6%) as colorless tar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:13]([O-:15])=[O:14].[CH3:16][N:17]([CH:19](N(C)C)OC(C)(C)C)[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:13]([O-:15])=[O:14])[C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1ccc(C)c([N+](=O)[O-])c1[N+](=O)[O-]
Product: COc1ccc(C=CN(C)C)c([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
57.7 g of 4-methoxy-2,3-dinitrotoluene (J. Chem. Soc. 1927:580) is agitated with 150 ml of bisdimethylamino-tert-butoxymethane [Chem. Ber. 101:41 (1968)] for 6 hours at 80° C. After cooling, the precipitated solid material is filtered off, washed with diisopropyl ether, and dried with a water-jet aspirator, thus producing 54.6 g of β-dimethylamino4-methoxy-2,3-dinitrostyrene, mp 100°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[N:9]2[CH:16]2[CH2:21][CH2:20][CH:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N+:29]([O-])=O)[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.O.NN>[Ni].CCO>[NH2:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[NH:22][CH:19]1[CH2:20][CH2:21][CH:16]([N:9]2[C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]([CH3:13])([CH3:14])[O:11][C:10]2=[O:15])[CH2:17][CH2:18]1
Reactant: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3[N+](=O)[O-])CC2)[C@H]1c1ccc(F)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1(C)OC(=O)N(C2CCC(Nc3ccncc3N)CC2)[C@H]1c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a flask charged with (S)-4-(4-fluorophenyl)-5,5-dimethyl-3-(4-((3-nitropyridin-4-yl)amino)cyclohexyl)oxazolidin-2-one (0.285 g, 0.665 mmol) was added EtOH (13.30 mL). Raney 3202 nickel (slurry in water) (0.733 mL, 111 mmol) was then added using a pipette. The flask was sealed, placed under nitrogen, and heated at 40° C. To the resulting yellow solution was added hydrazine hydrate solution (0.311 mL, 9.98 mmol) dropwise. The resulting mixture was stirred for 90 minutes at 40° C. LC-MS indicated complete conversion to the desired product. The mixture was cooled to room temperature, filtered through Celite® brand filter aid, and washed with MeOH. The filtrate was dried under reduced pressure and was then purified using a 5 g SCX-2 column washing with MeOH and then with 2 M NH3 in MeOH. The basic wash was dried under reduced pressure providing a brown oil which solidified after overnight under high vacuum to yield (S)-3-(4-((3-aminopyridin-4-yl)amino)cyclohexyl)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.213 g, 0.535 mmol, 80% yield) as a yellow solid. m/z (ESI) 399.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:35]([N:15]2[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=[C:14]2[C:8]2[C:9]([O:11][CH2:12][CH3:13])=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[N:6][CH:7]=2)=[O:36])[CH2:49][CH2:50]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-tert-butyl-2-piperazin-1-yl-acetamide (Enamine-BB) to give the title compound. HR-MS (ES, m/z) calculated for C38H50N7O3Cl2 [(M+H)+] 722.3347, observed 722.3341.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].C(=O)([O-])[O-].[Ca+2:11]>O>[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Ca+2:11].[Ca+2:11].[Ca+2:11]
Reactant: CC(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CC(O)C(=O)[O-]
Yield: 264.8 %

Procedure:
30 kg of 80% synthetic lactic acid are dissolved in 66 kg of water and refluxed for 15 hours. Next, 4.4 kg of calcium carbonate are added to the approximately 25% solution of lactic acid at a temperature of about 70° C., while stirring, and the clear solution is finally dried in a thin-layer evaporator at about 80° C. and 25-50 torr vacuum. 25.4 kg of pourable calcium hexalactate are obtained, corresponding to 98.9% of the theoretical quantity.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[I-].[Na+].Cl[Si](C)(C)[CH3:25]>C(#N)C.O>[CH3:25][C:10]1[NH:11][C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: C[Si](C)(C)Cl
Reactant: COc1ncc(-c2cccc(C#N)c2)c2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1[nH]c(=O)c2ccccc2c1-c1cccc(C#N)c1
Yield: 82.6 %

Procedure:
To a solution of 4-(3-cyanophenyl)-1-methoxyisoquinoline (200 mg, 0.73 mmol) in acetonitrile (6 mL) is added sodium iodide (219 mg, 1.46 mmol) followed by chlorotrimethylsilane (186 μL, 1.46 mmol) and the mixture is heated at reflux for 1.5 hr. The cooled reaction is diluted with water (15 mL) and the solids are collected by filtration, washed with water and dried to give 3-(3-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)benzonitrile (157 mg, 83% yield). 1H NMR (δ ppm) 11.55 (1H, s), 8.22 (1H, d), 7.95 (1H, d), 7.82 (1H, s), 7.72 (1H, t), 7.66 (1H, m), 7.60 (1H, m), 7.47 (1H, t), 6.94 (1H, d), 1.99 (3H, s).
Reaction SMILES: Cl.[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(OC([NH:35][C@@H:36]([CH2:40][C:41]1[S:42][CH:43]=[CH:44][CH:45]=1)[C:37](O)=[O:38])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([CH2:8][NH:9][C:10]([C:12]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][CH:20]=3)[CH2:13][CH2:14][N:15]([C:37](=[O:38])[C@@H:36]([NH2:35])[CH2:40][C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)O
Reactant: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CC2(C(=O)NCC3CCCCC3)CCN(C(=O)[C@@H](N)Cc3cccs3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethylamide hydrochloride (0.584 mmol; 0.23 g) in DMF (5 mL) was added (S)-2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionic acid (0.642 mmol; 0.174 g), N,N-diisopropyl-N-ethylamine (2.335 mmol; 0.413 mL) and HBTU (0.701 mmol; 0.266 g), and the resulting mixture was stirred at room temperature overnight. The mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (10 mL) was added. The resulting solution was stirred for 5 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-(2-(S)-amino-3-thiophen-2-yl-propionyl)-4-(4-carbamoylbenzyl)-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]2[N:7]([CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[CH:25][C:24]=3[CH:33]3[CH2:35][CH2:34]3)[C:8](=[O:21])[C@@H:9]([NH:13]C(=O)OC(C)(C)C)[C@H:10]([CH3:12])[NH:11][C:5]=2[CH:4]=1)#[N:2].[ClH:38]>O1CCOCC1.CCOCC>[ClH:38].[ClH:38].[NH2:13][C@@H:9]1[C:8](=[O:21])[N:7]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][C:24]=2[CH:33]2[CH2:35][CH2:34]2)[C:6]2[CH:36]=[CH:37][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[NH:11][C@H:10]1[CH3:12]
Reactant: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@H]1Nc2cc(C#N)ccc2N(Cc2c(C3CC3)cnc3ccccc23)C(=O)[C@H]1N
Reaction time: 2.5 h

Procedure:
A rt suspension of tert-butyl(3S,4S)-7-cyano-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (134 mg, 269 μmol) in 4 M HCl in dioxane (1.35 ml) was stirred for 2.5 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration to provide (3S,4S)-3-amino-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile dihydrochloride (127 mg, quant.) as an off-white solid. MS m/z 398 (MH)+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14](Cl)[N:13]=1.Cl>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)nc(OCc2ccccc2)c1
Reaction time: 1 h

Procedure:
With cooling with ice, benzyl alcohol (3.4 mL) was dropwise added to a DMF (100 mL) suspension of sodium hydride (3.2 g). This was stirred at that temperature for 1 hour, then a DMF (30 mL) solution of 2,6-dichloropyridine-4-carboxylic acid (6.38 g) was dropwise added to the reaction solution with cooling with ice, and stirred at that temperature for 1 hour and 30 minutes and then overnight at 90° C. With cooling with ice, diluted hydrochloric acid was added to it, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A mixed solution of hexane/ethyl acetate=2/1 was added to the residue, and the formed precipitate was removed. The filtrate was concentrated under reduced pressure to obtain the title compound as a yellow oil. Not purified, this was used in the next step.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C(OCC=CCO)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl oleate was prepared by the procedure of Example 1 from 19 gms (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 30 gms (0.1 mole) of oleoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[CH:30]=[O:31]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:34]3[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][C:27]=3[Br:26])=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N-(4-chlorophenethyl)-4-hydroxybenzamide (1.5 g, 5.4 mmol) was diluted with DMSO (15 mL) followed by the addition of K2CO3 (0.89 g, 6.4 mmol) and 3-bromo-4-fluorobenzaldehyde (1.0 g, 4.9 mmol). The reaction was stirred at 85° C. overnight and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and then concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (1:1) and then 100% ethyl acetate to yield N-(4-chlorophenethyl)-4-(2-bromo-4-formylphenoxy)benzamide (1.6 g, 71% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][CH2:49][NH2:50])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCCN)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCCCN)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(4-amino-butyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-4-[7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-3,4-dihydro-2H-quinolin-1-yl]-butylamine as a light yellow oil; MS: 588 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:25])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:31][C:32](=O)[CH2:33][C:34](=[O:54])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[C:45]([CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)=[CH:44][N:43]=[N:42]2)[CH:36]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH:14][C:32](=[O:31])[CH2:33][C:34](=[O:54])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]3[C:45]([CH2:46][O:47][CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][O:49]4)=[CH:44][N:43]=[N:42]3)[CH:36]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:24])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example J3) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl ]-phenyl}-propionic acid tert-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow solid (253 mg).
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:22]>[OH-].[NH4+]>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:22])=[CH:19][CH:18]=1
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 168 h
Yield: 56.5 %

Procedure:
To a 500 mL flask was charged 75.0 g (0.24 mole) of alpha-n-butyl-alpha-(4-chlorophenyl)-1H-1,2,4-triazole-1-propanenitrile followed by 300 mL of 95% sulfuric acid. The mixture was stirred at 90° C. for 7 days after which the mixture was cooled to room temperature, diluted with ice and neutralized with ammonium hydroxide until basic (pH 8). The product was extracted with ethylene dichloride then washed with water and dried over magnesium sulfate. The solvent was concentrated and gave 45 g (56.5% yield) of a solid melting point 197°-199° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.C[O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:30]4[CH:29]=[N:28][C:27]([OH:26])=[N:32][CH:31]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1ncc(B(O)O)cn1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cnc(O)nc1
Yield: 76.5 %

Procedure:
Using the conditions of General Procedure C for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-methoxypyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 77 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-hydroxy-pyrimidin-5-yl)-benzoic acid (85 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 13.40 (br s, 1H), 8.42-8.62 (m, 2H), 8.20-8.38 (m, 2H), 8.04-8.14 (m, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.61 (d, J=7.5 Hz, 1H).
Reaction SMILES: C1(O[C:8]#[N:9])C=CC=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:26]=[N:25][CH:24]=[C:23]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[C:18]=1[C:19]([NH:21][NH2:22])=[O:20]>CS(C)=O>[NH2:9][C:8]1[O:20][C:19]([C:18]2[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[Cl:10])=[CH:26][N:25]=[CH:24][C:23]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[N:21][N:22]=1
Reactant: N#COc1ccccc1
Reactant: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1Cl
Solvent: CS(C)=O
Product: Nc1nnc(-c2c(Nc3ccc(I)cc3F)cncc2-c2ccccc2Cl)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.6 %

Procedure:
Phenyl cyanate (5 mg, 0.04 mmol) was added to a solution of 3-(2-chloro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (7) (17 mg, 0.04 mmol) in DMSO (1 mL), and stirred overnight at room temperature. The reaction solution was quenched with H2O. The resulting precipitate was filtered, washed with H2O, and dried under vacuum to afford the desired product (5 mg, 28%). LC-MS (M+H=508, obsd.=508). 1H NMR: δ 8.92 (s, 1H), 8.47 (d, 1H), 8.03 (d, 1H), 7.74 (dd, 1H), 7.55 (m, 2H), 7.43 (m, 3H), 7.24 (t, 1H), 7.11 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>CN(C=O)C>[S:13](=[O:16])(=[O:15])([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[NH2:14]
Reactant: OCCc1ccc(Br)cc1
Reactant: NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)OCCc1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 57.1 %

Procedure:
A mixture of 2.95 g (0.015 mole) of 4-bromophenethyl alcohol in 10 ml DMF was added dropwise to a suspension of sodium hydride 0.90 g, 60% in oil; 0.065 mole) in 35 ml DMF at 0°-5° C. The suspension was stirred for 20 min under argon after which sulfamoyl chloride (2.09 g, 0.018 mole) was added portionwise at 0°-5° C. After stirring for 20 min, the resultant suspension was poured into ice and extracted twice with Et2O. The combined organic phases were washed with saturated brine, dried over potassium carbonate and concentrated in vacuo to a white solid which was recrystallized in EtOAc/hexane to give 2.40 g (59%) of the title compound as a white solid, mf 109°-110° C.