Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)[O:21][N:20]=1)(=[O:12])=[O:11].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C.ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]=[O:33])=[CH:30][CH:31]=2)[O:21][N:20]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(c1nc2ccccc2[nH]1)N1CCCCC1c1noc(COc2ccc(CO)cc2)n1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Tetrapropylammonium perruthenate (14.4 mg) was added to a stirred suspension of 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)phenylmethanol (384 mg) [see Preparation 21], N-methylmorpholine oxide (166 mg) and 4 Å molecular sieves in 10% v/v acetonitrile/dichloromethane (4 ml). The reaction mixture was stirred for 1 hour after which time the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate to afford 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzaldehyde (342 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2(O)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]([C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[CH:39]=4)=[CH:34][CH:33]=3)(O)[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=1.I.[PH2](O)=O>C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[C:23]([C:24]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:47]=[CH:46][C:45]6[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH:39]=5)=[CH:34][CH:33]=4)=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1
Reactant: OC1(c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc2C(O)(c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc2cc(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6ccc7ccccc7c6)cc5)c5ccccc45)cc3)ccc2c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
9,10-bis(4-(2-Naphthyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (3.5 g, 5.7 mmole) was suspended in acetic acid (80 ml). To the resultant suspension, a 57% hydroiodic acid (15 ml, 0.11 mole, 20 eq) was added and the obtained mixture was stirred at 100° C. for 7 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (3.3 g, 98%) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[N:10]=[C:11]([C:14]([NH2:16])=O)[S:12][CH:13]=1)(=[O:8])[CH3:7]>CN(C)C=O>[C:6]([C:9]1[N:10]=[C:11]([C:14]#[N:16])[S:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1csc(C(N)=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1csc(C#N)n1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
Phosphorus oxychloride (8.5 ml) was added slowly to a solution of 4-acetyl-2-thiazolecarboxamide (10.0 g) in N,N-dimethylformamide (500 ml) at 0°-5° C. with cooling on an ice-water bath. The mixture was stirred at 0°-5° C. with cooling on an ice-water bath for 4 hours and then was poured into ice water (400 ml). The solution was extracted with ethyl acetate (750 ml×2). The extract was dried with magnesium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from water to afford 4-acetyl-2-cyanothiazole (6.7 g).
Reaction SMILES: B(Br)(Br)Br.[CH3:5][N:6]1[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[C:12]([O:15]C)[CH:13]=2)[CH:8]=[C:7]1[C:18]1[C:23]([Cl:24])=[CH:22][C:21]([O:25]C)=[CH:20][C:19]=1[Cl:27]>O>[CH3:5][N:6]1[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[C:7]1[C:18]1[C:19]([Cl:27])=[CH:20][C:21]([OH:25])=[CH:22][C:23]=1[Cl:24]
Reactant: COc1cc(Cl)c(-c2cc3c(Cl)cc(OC)cc3n2C)c(Cl)c1
Agent: BrB(Br)Br
Solvent: O
Product: Cn1c(-c2c(Cl)cc(O)cc2Cl)cc2c(Cl)cc(O)cc21
Reaction time: 8 h

Procedure:
3.4 ml (35 mmole) of BBr3 were added with a syringe to a solution of 3.0 grams of 1-methyl-2-(2,6-dichloro-4-methoxy-phenyl)-4-chloro-6-methoxy-indole in 50 ml of water free methylene chloride at -70° C. After 30 minutes the cold bath was removed and the mixture was stirred overnight. The reaction mixture under ice cooling was carefully poured into a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off with suction, washed with water and reprecipitated from methanol/water. Yield: 2.4 grams.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]1[CH:26]([CH2:27][C:28]([OH:30])=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)(=[O:12])=[O:11].Cl.Cl.[NH:33]1[CH2:37][CH2:36][N:35]=[C:34]1[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][NH2:46])=[CH:40][CH:39]=1>>[NH:35]1[CH2:36][CH2:37][N:33]=[C:34]1[C:38]1[CH:39]=[CH:40][C:41]([CH2:44][CH2:45][NH:46][C:28](=[O:30])[CH2:27][CH:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]2[S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:11])=[O:12])=[CH:42][CH:43]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)O)c(C)c1
Agent: Cl
Product: Cc1cc(C)c(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)NCCc2ccc(C3=NCCN3)cc2)c(C)c1

Procedure:
The title compound was prepared from [5-(2,4,6-trimethyl-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].OO.[O:11]1[CH:16]([C:17]([OH:19])=[O:18])[CH:12]1[C:13]([OH:15])=[O:14]>>[CH:16]([OH:11])([C:17]([OH:19])=[O:18])[CH:12]([OH:5])[C:13]([OH:15])=[O:14]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: O=C(O)C1OC1C(=O)O
Agent: OO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
Thus free maleic acid is reacted in aqueous solution with hydrogen peroxide in the presence of alkali tungstates or molybdates, the intermediate epoxysuccinic acid formed hydrolyzed by boiling and then the racemic acid formed crystallized out of the hydrolysis solution, see Church and Blumberg, "Ind. Eng. Chem.", Vol. 43 (8) pages 1780 to 1786. The mother liquor of the racemic acid crystallization is again returned into the reaction step.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1>C1(C)C=CC=CC=1>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: Cc1ccccc1
Product: O=C(C(Cl)Cl)N1CCC2(CC1)OCCO2
Yield: 49.2 %

Procedure:
12.4 g (0.084 mol) of dichloroacetyl chloride was added dropwise to a mixture of 12 g (0.084 mol) of piperid-4-one ethylene ketal and 12.8 g (0.084 mol) of 1,8-diazobicyclo[5.4.0]undec-7-ene in 100 ml of toluene, whilst stirring, at a rate such that the temperature of the reaction mixture did not exceed 40° C. Thereafter, the mixture was subsequently stirred at 20° C. for 2 hours. Working up was then effected by a procedure in which the reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was recrystallized from a mixture of toluene and petroleum ether. 10.5 g (49% of theory) of N-dichloroacetylpiperid-4-one ethylene ketal were obtained in this manner in the form of colorless crystals of melting point 102° C.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].[N:31]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][S:35]([N:31]2[CH2:34][CH2:33][CH2:32]2)(=[O:37])=[O:36])[CH2:4]1)[CH3:2]
Reactant: O=S(=O)(Cl)N1CCC1
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)N2CCC2)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A flask was charged with (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.200 g, 0.471 mmol, Example #8, Step M) and DMF (4 mL). The solution was cooled to about 0° C. followed by the addition of TEA (0.16 mL, 1.2 mmol) and azetidine-1-sulfonyl chloride (0.165 g, 1.06 mmol, Preparation #CC.1). The reaction mixture was warmed to ambient temperature and was stirred for about 2 h. The solvent was removed under reduced pressure and DCM (10 mL) was added to the resulting residue. The organic solution was washed with water and brine (5 mL each). The combined organics were dried over anhydrous MgSO4, filtered, and concd under reduced pressure to give a brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to afford N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)-cyclopentyl)azetidine-1-sulfonamide (0.20 g, 77%) as a white solid: LC/MS (Table 1, Method a) Rt=2.39 min; MS m/z: 544 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.Cl.Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (800 mg, 2.68 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine dihydrochloride (692 mg, 3.21 mmol) to afford the desired product (629 mg, 58%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 10.77 (br d, J=8.1 Hz, 1H), 9.01 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 7.84-7.68 (m, 2H), 4.05-3.89 (m, 1H), 3.08 (q, J=7.2 Hz, 2H), 2.33 (s, 6H), 2.33-2.23 (m, 2H), 2.12-1.99 (m, 2H), 1.63-1.31 (m, 4H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:19])[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([O:8][CH2:9][C@@H:10]([O:19][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1)[C@@:11]([O:17][CH3:18])([CH3:16])[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC[C@@](C)(OC)[C@H](O)COCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC[C@@](C)(OC)[C@@H](COCc1ccccc1)OC1CCCCO1

Procedure:
A solution of (2R,3R)l-benzyloxy-3-methoxy-3-methyl-6-heptene-2-ol (10) (37.1 mmol, 9.8 g), dihydropyran (55.7 mmol, 5.1 ml) and pyridinium paratoluene sulfonate (3.71 mmol, 0.93 g) in anhydrous dichloromethane (100 ml) is stirred under nitrogen atmosphere for 24 h. Ether (400 ml) is added, and the organic layer is washed with water, brine, saturated aqueous NaHCO3 and brine. After drying over anhydrous magnesium sulfate the solvent is flash evaporated. The product 11b is used as such in the next reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1Cl.[CH:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=2[OH:20])[CH2:12][CH2:11]1.[OH-].[K+].Cl>CO.CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[N:4][C:3]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH:10]2[CH2:11][CH2:12]2)=[C:2]([OH:1])[CH:7]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Yield: 20.8 %

Procedure:
To a mixture of 301 mg (purity: 100%; 1.82 mmol) of 4-hydroxy-3,6-dichloropyridazine and 827 mg (5.49 mmol) of 2-cyclopropyl-6-methylphenol were added N-methylpyrrolidone (2.76 g) and 322 mg (5.46 mmol) of 95% potassium hydroxide at room temperature. The resultant mixture was heated to 180° C. while stirring, and stirred at that temperature for 4 hours. Then, the resultant reaction mixture was cooled to room temperature, and a 1 N aqueous hydrochloric acid solution and methanol were added to the reaction mixture to obtain a uniform solution. The obtained solution was quantitatively determined by an HPLC internal standard analysis method, which showed that 105 mg of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 21%) and 4.2 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.8%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:5][NH:6][C:7]([C:9]1([C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)=[O:8].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[CH2:5][NH:6][C:7]([C:9]1([C:16]2[CH:21]=[CH:20][C:19]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)=[O:8]
Reactant: CN1CCC(C(=O)NCc2cc(Cl)cc(Cl)c2)(c2ccc(I)cc2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCC(C(=O)NCc2cc(Cl)cc(Cl)c2)(c2ccc(-c3cccc(C#N)c3)cc2)CC1
Temperature: 25 °C
Yield: 8.8 %

Procedure:
To a solution of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid pyridine salt (0.44 g, 1.04 mmol, see Example 6) and 3,5-dichlorobenzylamine (0.22 g, 1.24 mmol, 1.2 eq) in anhydrous DMF (5 mL) was added DIC (0.326 mL, 2.08 mmol, 2 eq) followed by DMAP (0.006 g, 0.052 mmol, 5%). The mixture was stirred at room temperature for 16 h and then it was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated, washed with H2O (3×40 mL) and saturated brine (50 mL), dried over Na2SO4, filtered and concentrated by rotary evaporation. The crude material was purified by silica gel chromatography by eluting with 10% MeOH/EtOAc to give 60 mg (11%) of 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid. MS(ESI): 503.1/505.1. To a flask containing 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide (60 mg, 0.12 mmol) was added Pd(PPh3)4 (3.2 mg, 0.012 mmol, 10 mol %), 3-cyanophenylboronic acid (26.4 mg, 0.18 mmol, 1.5 eq.) and Na2CO3 (0.21 g, 2 mmol). The mixture was suspended in toluene (2 mL), EtOH (1 mL) and H2O (1 mL) and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (5 mL). The organic layer was washed with saturated Na2CO3 (3×5 mL), dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation. The crude product was purified by HPLC to give 4-(3′-cyano-biphenyl-4-yl)-1-methyl-piperidine-4-carboxylic acid 3,5-dichloro-benzylamide as a white solid (0.05 g, 0.0105 mmol, 10%). 1H NMR (300 MHz, CDCl3): δ 7.88 (m, 2H), 7.71 (m, 3H), 7.52 (d, 2H), 7.31 (t, 1H), 7.00 (dd, 2H), 6.55 (t, 1H), 4.55 (br, 1H), 4.44 (d, 2H), 3.76 (m, 2H). 3.32 (m, 2H), 2.94 (s, 3H), 2.86 (m, 2H). 2.52 (t, 2H). MS (ESI): 478.1/480.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)Nc2ccc3ccccc3n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 191A (91.6 mg, 0.4 mmol) in DMF (4 ml) was added 2-aminoquinoline (64 mg, 0.44 mmol), ED AC (93 mg, 0.48 mmol), HOBT (82 mg, 0.6 mmol), and diisopropylethylamine (0.35 ml, 2 mmol). The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2 times) and brine. The organic layer was dried (sodium sulfate), filtered, concentrated under reduced pressure and purified by flash chromatography with 3% methanol/dichloromethane to provide the titled compound. MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1>CS(C)=O>[N:1]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCC1CCCCO1
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC1CCCCO1
Temperature: 50 °C
Reaction time: 12 h
Yield: 87.8 %

Procedure:
A mixture of sodium azide (65 g, 1 mol), dimethylsulfoxide (800 ml), and 2-(bromomethyl)-tetrahydro-2H-pyran (89.5 g, 0.5 mol) is stirred at 50° C. for 12 hours. The reaction mixture is allowed cool to room temperature and then slowly poured into ice water. The reaction is extracted with ether (3×400 ml). The combined organic extracts are washed with water (500 ml) and then brine (500 ml), and dried over sodium sulfate. Removal of the volatiles in vacuo affords the pure title compound (62 g, 88%) as a colorless oil.
Reaction SMILES: [N:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])=[O:2].CS(O)(=O)=O.[OH2:15]>C(Cl)Cl>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:1]([C:6]1[CH:7]=[CH:8][C:3]([N:1]=[O:15])=[C:4]([CH3:9])[CH:5]=1)[OH:2]
Reactant: Cc1ccccc1N=O
Reactant: O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: Cc1cc(N(O)c2ccccc2C)ccc1N=O

Procedure:
4.982 g of 97% ortho-nitrosotoluene (41.12 mmol) were dissolved in 20 ml of methylene chloride at room temperature and 5.93 g of 98% methane sulfonic acid (61.7 mmol = molar ratio of 1:1.5) added thereto in the course of 2 minutes. Stirring was continued for one-half hour at room temperature and subsequently the dark brown, clear solution sprayed into water of 30° C. under a vacuum, whereby the methylene chloride was distilled off simultaneously. By means of filtration, it was possible to obtain 4.85 g = 97% of theoretical, of N-(2-methylphenyl)-N-(3-methyl-4-nitrosophenyl)-hydroxylamine in the form of a light yellow powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: C1CCNC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCCC2)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 52.7 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.287 mmol), pyrrolidine (Aldrich Chemical Company) (0.12 mL, 1.44 mmol) and K2CO3 (0.397 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by flash chromatography on silica gel with 20:1 CHCl3:MeOH as eluant to give 42.1 mg (53%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. 1H NMR (CDCl3; 500 MHz): δ 2.07 (t, 4, J=6.3), 2.58 (s, 3), 3.88-3.90 (m, 4), 6.71 (s, 1), 7.36-7.46 (m, 3), 7.63 (d, 2, J=7.7). MS m/z: 279.5 (M+1), 277.5 (M−1). HRMS: Calcd for M+H: 279.1610. Found: 279.1613.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[CH3:12][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH3:12][C:7]1([OH:10])[CH2:6][CH2:5][C:4]2([O:3][CH2:2][CH2:1][O:11]2)[CH2:9][CH2:8]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
1,4-cyclohexandione mono-ethylene ketal (1.0 g, 6.4 mmol) was dissolved in THF (30 ml), followed by addition of MeMgCl (3.0M solution in THF, 2.6 ml, 7.7 mmol) at 0° C., and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. A saturated aqueous ammonium chloride solution was added to the resulting reaction liquid, followed by extraction with MC (50 ml×2). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 654 mg of white solid (59%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([F:11])[CH:4]=1.[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][NH:19][S:20]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:11][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH3:10])[CH2:2][N:19]([CH2:18][C:17]1[CH:33]=[CH:34][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)(=[O:22])=[O:21]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CBr)cc1F
Product: COc1ccc(CN(Cc2ccc(OC)c(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from 4-(bromomethyl)-2-fluoro-1-methoxybenzene and methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (example 5-10b). MS (M−H, 458.10); 1H NMR (400 MHz, CD3OD): δ, ppm: 3.73 (s, 3H), 3.80 (s, 3H), 4.24 (s, 2H), 4.28 (s, 2H), 6.75 (m, 4H), 6.88 (m, 1H), 6.97 (d, 2H, J=8.6 Hz), 7.88 (d, 2H, J=8.3 Hz), 8.14 (d, 2H, J=8.3 Hz).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([O:15][CH2:16][CH:17]([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH3:20]O>>[Cl:5][C:6]1[C:7]([O:15][CH2:16][CH:17]([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=1)[C:11]([O:13][CH3:20])=[O:12]
Reactant: O=C(O)c1cnc(OCC(F)F)c(Cl)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc(OCC(F)F)c(Cl)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
Thionyl chloride (1.38 ml, 18.9 mmol) is added to a solution of 5-chloro-6-(2,2-difluoroethoxy)nicotinic acid (1.5 g, 6.31 mmol, Step-1) in methanol (100 ml) at 0° C. Then the reaction mixture is refluxed with stirring for 2 hours. After removing solvent to give 1.57 g (>99% yield) of the title compound as white solid.