Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1cnc(-c2ccc(Br)cc2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)cc1
Temperature: 70 °C

Procedure:
5-(4-Bromophenyl)pyrazin-2-amine (51 mg, 0.20 mmol), (2-(methylsulfonyl)phenyl) boronic acid (61 mg, 0.31 mmol), K2CO3 (85 mg, 0.61 mmol) and Pd(dppf)Cl2.CH2Cl2 (15 mg, 0.020 mmol) were weighed into a sealable vial containing a stir-bar. The vial was sealed and evacuated before backfilling with argon and adding deoxygenated DMSO (0.8 mL). The vial was heated at 70° Celsius for 3 hours by which point the starting material had been consumed. The vial was cooler to rt, diluted with MeOH (1 mL), filtered with a syringe filter, and the filtrate subjected to HPLC purification to provide the title compound. MS (ESI): mass calcd. for C17H15N3O2S, 325.39; m/z found, 326.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J=8.1, 1.4, 2H), 8.26 (dd, J=8.0, 1.4, 1H), 8.00-7.90 (m, 2H), 7.74-7.64 (m, 1H), 7.64-7.56 (m, 3H), 7.41 (dd, J=7.5, 1.4, 1H), 2.70 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[NH:13][C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH:15]([NH:16][C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[O:18])[C:14](=[O:29])[N:13]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:12]3[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2Sc3ccccc3NC(=O)C2NC(=O)c2ccc3ccccc3c2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)C(NC(=O)c2ccc3ccccc3c2)C(c2ccc(OC)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In the same manner as in (iv) of Example 1, 1.5 g of 2-p-methoxyphenyl-3-(2-naphthalenecarboxamido)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is dissolved in 30 ml of dimethylformamide, whereto 0.145 g of 60% sodium hydride is added under ice-cooling. After the mixture is stirred at room temperature for 30 minutes, 5 ml of dimethylformamide containing 0.45 ml of ethyl bromoacetate is added dropwise. The mixture is stirred at room temperature for 3 hours, and then the reaction mixture is concentrated under reduced pressure. Chloroform and water are added to the residue to separate the organic layer. The chloroform layer is washed with water and dried. The solvent is distilled off under reduced pressure. A mixed solvent of isopropyl alcohol-isopropyl ether is added thereto. The resulting crystals are collected by filtration to give 1.8 g of ethyl 2-p-methoxyphenyl-3-(2-naphthalenecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetate, m.p. 183°-186° C.
Reaction SMILES: C1(N=C=O)C=CC=CC=1.[CH:10]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])=[CH2:11].[C:18]1([CH2:24][CH2:25][N+:26]([O-])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:24]([C:25]1[CH2:11][CH:10]([P:12](=[O:17])([O:15][CH3:16])[O:13][CH3:14])[O:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CP(=O)(OC)OC
Reactant: O=[N+]([O-])CCc1ccccc1
Agent: N
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: COP(=O)(OC)C1CC(Cc2ccccc2)=NO1
Reaction time: 8 h

Procedure:
13.5 ml (0.124 mol) of phenyl isocyanate, 9.5 g (0.07 mol) of dimethyl vinylphosphonate and 1 ml of triethylamine are introduced into 120 ml of toluene. A solution of 9.3 g (0.062 mol) of 2-phenylnitroethane and 1 ml of triethylamine dissolved in 150 ml of toluene is added dropwise in 5 hours, the mixture is stirred overnight and then for 30 minutes after addition of 30 ml of concentrated aqueous ammonia, precipitated diphenylurea is removed by filtration and washed with ethyl acetate, and the combined organic phases are extracted by shaking successively with water, 2 N hydrochloric acid and water, and are dried and concentrated. 13.9 g of reddish brown oil remain.
Reaction SMILES: C([O:8][C:9](=O)[NH:10][C:11]1[S:15][C:14]2[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:13]=2[CH:12]=1)C1C=CC=CC=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1>O1CCOCC1>[CH3:21][O:20][C:19]1[C:13]2[CH:12]=[C:11]([NH:10][C:9]([N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[O:8])[S:15][C:14]=2[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:18]=1
Reactant: C1CSCCN1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCSCC3)cc12
Yield: 47.7 %

Procedure:
A stirred solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester (200 mg, 0.513 mmol) in dioxane (5 ml) was heated with thiomorpholine (10 eq., 5.13 mmol) for 68 h at reflux under argon. After cooling the reaction the solvents were evaporated and the residue was chromatographed over silica gel eluting with heptane/EtOAc (1:2). The product fractions were then combined, evaporated and dried under vacuum at 60° C. to afford the pure title product (94 mg, 47% yield) as a light brown solid MS m/e=383.2 (M−H).
Reaction SMILES: [O-]CC.[Na+].Cl[C:6]1[N:7]([CH2:14][CH2:15][C@@H:16]([OH:29])[CH2:17][O:18]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[N:10]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[H-].[Na+]>CN(C)C=O.O.C(O)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:48]=[CH:47][C:46]([O:18][CH2:17][C@@H:16]3[O:29][C:6]4=[N:10][C:9]([N+:11]([O-:13])=[O:12])=[CH:8][N:7]4[CH2:14][CH2:15]3)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CCn2cc([N+](=O)[O-])nc2Cl)cc1
Agent: CC[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
An ethanol solution (3.02 ml) of 20% sodium ethoxide was added to an ethanol solution (30 ml) of toluene-4-sulfonic acid (R)-4-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxybutyl ester (3.00 g), and the mixture was stirred at room temperature for 30 minutes. 4-(4-Hydroxyphenyl)piperazine-1-carboxylic acid tert-butyl ester (2.36 g) and tripotassium phosphate (1.80 g) were added to the reaction mixture and heated under reflux for 4 hours. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dimethylformamide (46 ml), sodium hydride (0.31 g) was added thereto, and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over magnesium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=0:1) and recrystallized from acetone to afford the title compound as a yellow powder (0.72 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][NH2:12])=[C:4]([F:13])[CH:3]=1.[C:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)(=O)[CH3:15].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:14]([CH3:15])=[C:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:12]2)=[C:4]([F:13])[CH:3]=1
Reactant: CC(=O)C1CCCCC1=O
Reactant: NNc1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1cc([N+](=O)[O-])c(Cl)cc1F)CCCC2
Yield: 38.2 %

Procedure:
In the same manner as in Example 6 but using 4-chloro-2-fluoro-5-nitrophenylhydrazine (4 g), 2-acetylcyclohexanone (2.8 g), a catalytic amount of acetic acid and xylene (10 ml), there was produced 2.3 g of 2-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 143°-144° C.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O-:16])=[O:15])[CH:12]=2)[O:7][CH:6]=[CH:5]1.O.Cl>CO>[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[O:7][CH:6]=[CH:5]1
Reactant: O=C([O-])c1ccc2occc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2occc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.7 %

Procedure:
NaOH (3.56 mL, 7.11 mmol) was added to a stirred suspension of methyl 8-(1-hydroxyethyl)-2-(R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylate (988 mg, 2.84 mmol) in MeOH (10 mL)/water (10 mL). The resulting mixture was stirred at RT for 1 hour then acidified to pH 2-3 with a 2N aq. HCl (7.68 mL, 7.68 mmol). The resulting precipitate was collected by filtration, washed with diethyl ether and dried to afford 8-(1-hydroxyethyl)-2-(R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (900 mg, 95%) as a grey solid, which was used without further purification. Mass Spectrum: M+H+ 334.
Reaction SMILES: C([C:3](Br)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])C.[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[NH:14][CH:3]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5])=[O:21]
Reactant: CCC(Br)(C(=O)O)c1ccccc1
Reactant: COC(=O)c1sccc1N
Solvent: CC#N
Product: COC(=O)c1sccc1NC(C(=O)O)c1ccccc1

Procedure:
A solution of ethyl 2-bromo-2-phenylacetic acid (600 mg, 2.79 mmol) and methyl 3-aminothiophene-2-carboxylate (438 mg, 2.79 mmol) in acetonitrile (20 ml) was heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated to dryness and the resulting residue was used in the next step without any further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13]CC)=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:20][CH2:19][CH2:18][NH2:21])=[O:13])=[CH:16][CH:17]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Reactant: NCCN
Product: CC(=O)Nc1ccc(OCC(=O)NCCN)cc1

Procedure:
In a similar manner using 23.7 g. of ethyl 4-acetamidophenoxyacetate and 60 ml. of ethylenediamine as starting materials there is obtained β-(4-acetamidophenoxyacetamido)ethylamine, m.p. 210°-212° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:37]3([OH:44])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH:34]=2)[CH2:29]1)=[O:27])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:37]3([OH:44])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH:34]=2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3ccc(C4(O)CCN(C)CC4)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(C(=O)N2Cc3ccc(C4(O)CCN(C)CC4)cc3C2)c(O)cc1O
Yield: 101 %

Procedure:
(2,4-Bis-benzyloxy-5-isopropenyl-phenyl)-[5-(4-hydroxy-1-methyl-piperidin-4-yl)-1,3-dihydro-isoindol-2-yl]-methanone (Example 50F) (1.62 g, 2.75 mmol) was dissolved in methanol (50 mL) and hydrogenated at 50° C. over 10% palladium on charcoal using an H-cube hydrogenation apparatus, under free hydrogen conditions. Concentration afforded the title compound (1.14 g, 100%) as a yellow solid, the NMR and mass spectrometric data of which were as set out in Example 50E.
Reaction SMILES: [CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[C@H:6]([NH:9][C:10]([C@H:12]([NH2:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:11])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23].O.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40](Cl)=[O:41])[C:36](=[O:43])[C:35]1=[O:44])[CH3:33]>C(OCC)(=O)C>[CH3:1][C:2]1[CH2:21][S:20][C@@H:5]2[CH:6]([NH:9][C:10](=[O:11])[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:19][C:40]([N:37]3[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[C:35](=[O:44])[C:36]3=[O:43])=[O:41])[C:7](=[O:8])[N:4]2[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1CCN(C(=O)NC(C(=O)NC2C(=O)N3C(C(=O)O)=C(C)CS[C@H]23)c2ccccc2)C(=O)C1=O
Yield: 55.1 %

Procedure:
Cephalexin (696 mg., 2 mmoles) was dissolved in 10 ml. of water at 5° C. by the action of potassium carbonate (304 mg., 2.2 mmoles). Ethyl acetate (5 ml.) was added and then 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride (450 mg., 2.2 mole) was added over a period of 15 minutes at 0°-5° C. After addition was complete, the reaction mixture was stirred for an additional 30 minutes, at which time the ethyl acetate layer was separated and the aqueous phase washed with an additional portion of ethyl acetate. The aqueous phase was adjusted to 2.5 and the product extracted into several portions of fresh ethyl acetate. The acidic ethyl acetate extracts were combined, back-washed with water, washed with brine, dried over anhydrous magnesium sulfate, evaporated to dryness in vacuo, and the residue crystallized from methylene chloride to yield 3-methyl-7-[2-phenyl-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)acetamido]ceph-3-em-4-carboxylic acid (568 mg., m.p. 199°-200° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1.[NH2:17][N:18]1[C:27](=O)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH3:29])[CH:25]=2)[N:20]=[C:19]1NN.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[NH2:17][N:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([CH3:29])=[CH:25]2)=[N:20][CH:19]1[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCN(CCCCN)CC1
Reactant: Cc1ccc2nc(NN)n(N)c(=O)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(CCCCNC2N=c3ccc(C)cc3=CN2N)CC1
Temperature: 180 °C

Procedure:
A mixture of 10 g of ethyl 4-(4-aminobutyl)-piperazine-1-carboxylate, 5 g of 3-amino-2-hydrazino-6-methylquinazolin-4-(3H)-one and 0.5 g of p-toluenesulfonic acid was heated to 180° C. (bath temperature of reaction mixture 160° C.) for 4 hours. After cooling to 100° C., the reaction mixture was dissolved in 250 ml of toluene and was washed twice with 100 ml of water. The mixture filtered through `celite` and the product was retained in the toluene solution for use in the next stage.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12]>O=[Pt]=O.C(O)(=O)C>[NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)C1CCC2CCCCC2N1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
A mixture of quinoline-2-carboxylic acid (30 g, 0.17 mole), glacial acetic acid (1000 ml), and PtO2 (2.0 g) was subjected to hydrogenation at room temperature for 3 hours using 51.7 psia H2 (theory: 58.7 psia H2). The catalyst was removed by filtration and the filtrate was stripped of solvent under reduced pressure. The residue was dissolved in acetonitrile (300 ml) and the mixture was cooled. The product was collected by filtration and washed with acetonitrile and ether; m.p. 254°-258°; yield: 20 g. The filtrate was diluted with ether, cooled, and the product was collected by filtration. The two products were combined to give 23 g (74%) of decahydroquinoline-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([OH:17])[CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:10][CH2:11][C@@H:12]2[C@@H:16]([O:17][CH3:35])[CH2:15][CH2:14][O:13]2)=[CH:7][CH:8]=1
Reactant: CI
Reactant: COc1ccc(C(OC[C@H]2OCC[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@H]2OCC[C@@H]2OC)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.9 %

Procedure:
The product from Example 22C (620 mg, 1.47 mmol) in DMF (5 mL) was treated with NaH (60%)(88 mg, 2.2 mmol). The mixture was stirred for 10 min at rt. To the mixture was added dropwise iodomethane (251 mg, 1.57 mmol). The reaction was stirred at rt for 12 hrs. The reaction mixture was quenched with water and extracted with EtOAc. The organic was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 574 mg (90%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.91-2.02 (m, 2H) 3.09 (dd, J=9.82, 5.52 Hz, 1H) 3.15 (dd, J=9.82, 4.91 Hz, 1H) 3.31 (s, 3H) 3.78 (s, 6H) 3.81-3.93 (m, 2H) 3.94-4.06 (m, 2H) 6.77-6.87 (m, 4H) 7.16-7.23 (m, 1H) 7.26-7.37 (m, 6H) 7.40-7.48 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].[N+:13]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:5]1([CH3:12])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([N+:13]([O-:15])=[O:14])[CH:21]=3)[CH:3]=2)[NH:7][CH2:6]1
Reactant: CC1(C)CNc2ccc(Br)cc21
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)CNc2ccc(-c3cccc([N+](=O)[O-])c3)cc21
Yield: 57.6 %

Procedure:
Using the standard coupling conditions given in Example 1, the title compound was prepared from 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (0.25 g, 1.1 mmol), tetrakis(triphenylphosphine) palladium (0.08 g, 0.07 mmol) in dimethoxyethane (5 mL) with 3-nitrophenylboronic acid (0.22 g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) in 5 mL water. The title compound (0.17 g, 60%) was obtained as a brown semi-solid: 1H NMR (CDCl3) δ 1.38 (s, 3H), 3.40 (s, 2H), 6.72 (d, J=8.0 Hz, 1H), 7.29-7.34 (m, 2H), 7.54 (dd, J=8.0, 8.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.09 (dd, J=8.0, 1.5 Hz, 1H), 8.40 (dd, J=2.0, 2.0 Hz, 1H); 13C-NMR (CDCl3) δ 27.89 (q), 41.93 (s), 62.05 (d), 109.78, 120.87, 121.02, 121.23, 126.87 (d), 129.19 (s), 129.69, 132.52 (d), 139.64, 143.75, 148.94, 151.17 (s); MS (EI) m/z 268 (M)+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[OH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CC(C)=O.C(Cl)Cl>[C:4]([O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][CH2:14]1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(=O)CC(=O)OCCOCCN1CCC(c2ccccc2)(c2ccccc2)CC1

Procedure:
20 ml of a 50% strength solution of diketene in acetone are added dropwise to 32.5 g of N-[2-(2-hydroxyethoxy)-ethyl]-4,4-diphenylpiperidine and about 0.1 g of N,N-dimethylaminopyridine in 200 ml of methylene chloride at the boiling point, with vigorous stirring. After boiling under reflux for 1 h, the solution is allowed to cool and is concentrated to constant weight under a high vacuum. The pale yellow viscous coil which remains is used for the next stage without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12].[F:18][C:19]([F:30])([F:29])[O:20]C1C=C(C=CC=1)CN.COC(OC)C(OC)=O>>[CH3:12][O:11][CH:10]([O:13][CH3:14])[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([O:20][C:19]([F:30])([F:29])[F:18])[CH:16]=1)=[O:15]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: COC(OC)C(=O)NCc1cc(Cl)ccc1F
Agent: COC(=O)C(OC)OC
Product: COC(OC)C(=O)NCc1cccc(OC(F)(F)F)c1

Procedure:
By following the procedure for the preparation of N-(5-chloro-2-fluorobenzyl)-2,2-dimethoxyacetamide, the title compound was prepared from 3-(trifluoromethoxy)benzylamine (4.0 g, 21 mmol) and methyl dimethoxyacetate (2.8 g, 21 mmol). 1H NMR (CDCl3, 300 MHz): δ=3.40 (s, 6H), 4.44 (d, J=4.2 Hz, 2H), 4.75 (s, 1H), 6.95 (bs, 1H), 7.11 (s, 2H), 7.20 (d, J=2.4 Hz, 1H), 7.35-7.40 (m, 1H).
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:30])=[CH:5][CH:6]=4)[CH:14]=3)=[C:19]([C:20]([F:21])([F:22])[F:23])[O:18][N:17]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 80 %

Procedure:
As described for Example 10, 4-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid methyl ester (80 mg, 0.19 mmol) was converted, using 4-aminotetrahydropyran instead of cyclopropanemethylamine, to the title compound (75 mg, 80%) which was obtained as a white foam. MS: m/e=483.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1.Cl[C:19]1[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:19]2[N:24]=[C:23]([NH2:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[N:6]=1
Reactant: Fc1ccccc1Cc1n[nH]c2ncccc12
Reactant: Nc1nc(N)nc(Cl)n1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1nc(N)nc(-n2nc(Cc3ccccc3F)c3cccnc32)n1

Procedure:
A solution of 150 mg (0.66 mmol) of 3-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine from example 12A, 96 mg (0.66 mmol) of 6-chloro-1,3,5-triazine-2,4-diamine, 12 mg (0.013 mmol) of tris(di-benzylideneacetone)dipalladium, 19 mg (0.040 mmol) of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (XPHOS) and 300 mg (0.92 mmol) of cesium carbonate in 4 ml of degassed toluene is heated at 90° C. for 20 h. It is then diluted with water and a little methanol and extracted with ethyl acetate. The organic phase is concentrated in vacuo, and the residue is stirred with methanol and filtered off with suction. 62 mg (28% of theory) of the desired compound are obtained as beige-colored crystals in this way.