Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36]>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:52][CH2:51][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:55][CH2:54]2)([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(OC)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.3 g, 1.0 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.52 g, 1.0 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.38 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[CH2:2][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1cccc(Cl)c1CCl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cccc(Cl)c1CC#N
Yield: 55.1 %

Procedure:
A solution of 9.4 g of alpha,2-dichloro-6-methyltoluene in 30 ml of 95% ethanol is treated with a solution of 3.8 g of potassium cyanide in 5 ml of water and heated at reflux for 6 hours. The crude product is isolated by pouring the cooled reaction mixture into water and filtering the precipitated solid. Recrystallization from aqueous ethanol gives 4.9 g of pure 2-chloro-6-methylphenylacetonitrile, mp 49°-51° C., in two crops.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:6][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](OCC)=O.P(Cl)(Cl)(Cl)=O.Cl([O-])(=O)(=O)=[O:24].[Na+].[CH3:29][NH:30][C:31](=O)[CH3:32]>>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:32][CH:31]1[N:30]([CH3:29])[CH:13]=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N+:6]1=[O:24]
Reactant: CNC(C)=O
Reactant: CCOC(=O)c1cccc[n+]1N
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC1N(C)C=C2C=CC=CN2[N+]1=O
Yield: 83 %

Procedure:
To a solution of 12 g (45 millimoles) of 1-amino-2-carbethoxy-pyridinium perchlorate in 25 ml of N-methyl-acetamide 20 ml of phosphorus oxychloride are added at 90° C. The reaction mixture is allowed to stand for an hour, thereafter poured onto ice, the aqueous solution is saturated with sodium perchlorate and the separated product is filtered off. 10.3 g (83%) of 2,3-dimethyl-1-oxo-pyrido[2,1-f]-as-triazinium perchlorate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:13]([C:19]#[N:20])=[N:14][CH:15]=[C:16](Cl)[CH:17]=1.CN(C)C=O.CCCCCCC>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].C([O-])([O-])=O.[K+].[K+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:17]=[C:12]([Cl:11])[C:13]([C:19]#[N:20])=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncc(-c2cccc(Cl)c2)cc1Cl
Temperature: 5 °C
Yield: 64.5 %

Procedure:
A 20 L reactor equipped with a mechanical stirrer, dip tube, thermometer and nitrogen inlet was charged with (3-chlorophenyl)boronic acid (550 g, 3.52 mol), 3,5-dichloro-2-cyanopyridine (639 g, 3.69 mol), K2CO3 (5.5 g, 40 mmol), [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl2(dppf)] (11.5 g, 140 mmol), and dimethylformamide (3894 g, 4.125 L). The reaction solution was agitated and purged with nitrogen through the dip-tube for 30 minutes. Degassed water (413 g) was then charged to the reaction mixture while maintaining a temperature of less than 50° C. 25 hours. The reaction was determined to be complete due to the disappearance of 3,5-dichloro-2-cyanopyridine as measured by TLC analysis using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction solution was then cooled to 5° C. and charged with heptane (940 g, 1.375 L) and agitated for 30 minutes. Water (5.5 L) was charged and the mixture was further agitated for 1 hour as the temperature was allowed to rise to 15° C. The solid product was isolated by filtration and washed with water (5.5 L) followed by heptane (18881 g, 2750 ML). The resulting cake was air dried under vacuum for 18 hours and then triturated with a mixture of 2-propanol (6908 g, 8800 mL0 and heptane (1 g, 2200 mL0 at 50° C. for 4 hours, cooled to ambient temperature and then agitated at ambient temperature for 1 hour. The product was then isolated by filtration and washed with cold 2-propanol (3450 g, 4395 mL) followed by heptane (3010 g, 4400 mL). The resulting solid was dried under high vacuum at 40° C. for 64 hours to afford 565.9 g (65% yield) of the desired product as a beige solid. Purity by HPLC was 98.3. 1H NMR (DMSO-d6) δ 9.12 (d, 1H), 8.70 (d, 1H), 8.03 (t, 1H) 7.88 (m, 1H), and 7.58 (m, 2H).
Reaction SMILES: C[O-].[Na+].[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:18]1[CH2:22][CH:21]=[CH:20][CH:19]=1>>[C:5]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:21]2[CH:20]=[CH:19][CH:18]=[CH:22]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1=CCC=C1
Agent: C[O-]
Agent: [Na+]
Product: C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reaction time: 2 h
Yield: 82 %

Procedure:
78.0 g (0.24 mol) of sodium methylate solution were initially introduced into a 500 ml four-necked flask at 50° C. and 45.6 g (0.25 mol) of benzophenone were then added. After complete dissolution, 20 g (0.30 mol) of freshly distilled cyclopentadiene were added dropwise in the course of 30 min at 45-50° C. After the end of the addition, stirring was effected for a further 2 h at room temperature, a dark red suspension forming. This was filtered over a G3 frit and the solid was washed four times with 25 ml of ethanol each time. After drying in a vacuum from an oil pump, 47.1 g (0.20 mol; 82% yield) of red 6,6-diphenylfulvene were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:21]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccccc1-c1ccccc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 2-(bromomethyl)-1,1′-biphenyl. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 402.15 g/mol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[OH:10])=[O:6].[CH3:31][N:32]=[C:33]=[O:34]>ClC(Cl)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:10][C:33](=[O:34])[NH:32][CH3:31])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@@H](O)COC(=O)CCCCl
Reactant: CN=C=O
Solvent: CC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)CCCCl)OC(=O)NC

Procedure:
A solution of 0.33 g of (R)-1-O-(4-chlorobutyryl)-3-O-octadecylglycerine in 10 ml of dichloroethane is treated at 80° C. with 10 ml of methyl isocyanate. The solution is evaporated and the residue is chromatographed on silica gel while eluting with ether. There is obtained (R)-1-O-(4-chlorobutyryl)-2-O-(methylcarbamoyl)-3-O-octadecylglycerine of melting point 61°-62° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8]2)=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].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.C(O)C>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:8]3)=[CH:4][CH:3]=2)=[CH:24][CH:23]=1
Reactant: Brc1ccc(CN2CCOC(c3ccccc3)C2)cc1
Reactant: Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccc(CN3CCOC(c4ccccc4)C3)cc2)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
91 mg of 4-(4-Bromo-benzyl)-2-phenyl-morpholine was combined with 56 mg of 4-Methylphenyl boronic acid, 16 mg of tetrakis(triphenylphosphine)palladium(0), 0.92 mL of 2M sodium carbonate solution, 2.5 mL toluene and 1.23 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with 4 mL DCM and 130 mg of MP-TsOH resin (4.2 mmol/g loading) was added and the mixture agitated at room temperature overnight. The solution is filtered and the resin is then washed with 2M N3 in methanol to liberate product. The resin is washed several times with methylene chloride, concentrated in vacuo and purified by reverse phase HPLC. 18.5 mg of product was obtained as oil. ES MS m/z 344, 20% yield
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([NH:14][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]1([N:42]=[C:43]=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:43](=[O:44])[NH:42][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:11][CH2:10][N:9]1[C:26](=[O:35])[C:27]1[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Product: O=C(Nc1ccccc1)N(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.396 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine are reacted with 45 mg (0.377 mmol) of phenyl isocyanate in analogy to Example 16a. The title compound ##STR80## is obtained as solid residue (129 mg, 52%). TLC:methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.42, FD-MS:M+ =622, 624.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[CH2:14].ClCCC1C=CC=CC=1.P(=O)(O)(O)O>>[CH3:14][CH:13]1[C:12]2[C:11](=[CH:10][CH:17]=[CH:16][CH:15]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1cccc(Cl)c1
Reactant: C=Cc1ccccc1
Agent: ClCCc1ccccc1
Agent: O=P(O)(O)O
Product: CC1CC(c2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution containing 90 parts of styrene, 174 parts of m-chlorostyrene and 126 parts of m-chloroethylbenzene is added to 722 parts of 93 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours. After completion of the addition, the emulsion is stirred for 2 hours at 35° to 40° C. The organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation gives 27 parts of 1-methyl-3-phenylindan, 71 parts of 1-methyl-3-(m-chloro)-phenylindan (b.p. 168° to 172° C (10 mm), nD25 : 1.5872) and 23 parts of 1-methyl-3-(m-chloro)-phenyl-6-chloroindan (b.p. 197° to 204° C (10 mm)).
Reaction SMILES: C(O[C@H:5]1[CH2:9][C@@H:8]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:6]1)(=O)C.[BH4-].[Na+].C(O)(=O)C>C(O)(C)C.O1CCCC1.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>[CH3:16][C:14]([CH3:17])([O:13][C:11]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:8]1[CH2:9][CH2:5][CH:6]=[CH:7]1)=[O:12])[CH3:15]
Reactant: CC(=O)O[C@@H]1C=C[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C=CCC1
Yield: 79.2 %

Procedure:
To a solution of (1S-cis)-4-(di-tert-butoxycarbonylamino)cyclopent-2-enyl acetate (prepared as described by D. Zhang et.al. Tett. Lett. 1996, 3799–3802) (8.98 g), tetrakis(triphenylphosphine)palladium(0) (0.463 g) in isopropanol (135 ml) and tetrahydrofuran (135 ml) was added sodium borohydride (4.97 g) portionwise at 0° C. The mixture was stirred at 0° C. for 3 hours before the careful dropwise addition of glacial acetic acid (20 ml). The solution was concentrated in vacuo and the residue purified by chromatography (SiO2, diethylether 1:9 isohexane as eluent) to afford the sub-title compound (5.90 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].I[CH3:14]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.6 %

Procedure:
In an oven dried, nitrogen purged, 3 neck, 50 mL round bottom flask, 1.00 g (7.40 mmol) of 5-fluoroindole in 10 mL of dry dimethylformamide is reacted with 0.335 g (8.88 mmol) of 60% sodium hydride dispersed in mineral oil at room temperature for 4 h. 0.553 mL (8.88 mmol) of iodomethane is added and the reaction is allowed to stir at room temperature overnight, 15 h. The reaction is quenched with 50 mL of water, extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated. The crude product is purified by chromatography using hexanes:ethyl acetate as a solvent system to obtain 1.00 g of the title compound, 91% yield. MS, ES+218.2 (M+1); 1H NMR (DMSO-d6) δ 7.428-7.366 (m, 1H); 7.293-7.262 (m, 1H); 6.988-6.937 (m, 1H); 6.384-6.376 (m, 1H); 3.766 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[F:35][C:20]1[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]
Reactant: CC(C)CN
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cccnc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B, using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide (155 mg, 0.291 mmol) and isobutylamine (0.292 mL, 2.91 mmol) the title compound was obtained as a yellow foam (83 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.73 (dd, 1H), 8.03-8.13 (m, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.53 (dd, J=8.1, 4.9 Hz, 1H), 7.31-7.44 (m, 1H), 7.17-7.34 (m, 2H), 7.09 (d, J=1.4 Hz, 1H), 5.39-5.65 (m, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.36-3.49 (m, 4H), 2.82-3.14 (m, 2H), 1.77 (dt, J=13.3, 6.7 Hz, 1H), 0.82 (d, J=6.6 Hz, 6H). MS (ESI): 570.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.CC1(C)C(C)(C)OC([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH:23]=2)=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)cc1C=O
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: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(C=O)c3)cn2)CC1
Temperature: 25 °C

Procedure:
150 mg (0.605 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 413 mg (1.089 mmol) of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate are dissolved in 2.3 ml of N,N-dimethylformamide in a nitrogen-filled microwave vessel, and 1.7 ml (3.4 mmol) of 2M sodium carbonate solution and 35 mg (0.030 mmol) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction solution is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature and filtered. The filtrate is evaporated to dryness. The oily residue is purified by means of RP-HPLC, giving tert-butyl 4-[4-(6-amino-5-formylpyridin-3-yl)pyrazol-1-yl]-piperidine-1-carboxylate; HPLC-MS [M+H]+ 372.2.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[C:5]1=[O:30])[CH:2]=C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[C:5](=[O:30])[C@:4]([CH2:1][CH:2]=[O:33])([CH3:31])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrimidin-4-yl)piperidin-2-one (Example 110, Step B) (60 mg, 0.13 mmol) in a mixture of tetrahydrofuran (2.7 mL) and water (880 μL) was added osmium tetroxide (1.7 mg, 6.6 μmol). After 5 minutes, sodium periodate (89 mg, 0.46 mmol) was added and the reaction mixture was stirred for 14 hours. The reaction mixture was filtered through Celite® (J. T. Baker, Phillipsberg, N.J., diatomaceous earth) and washed with EtOAc and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 75% EtOAc/hexanes, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[C:12](Cl)[CH:11]=[C:10]([Cl:15])[N:9]=1.Cl>C1COCC1.[OH-].[Na+]>[Cl:7][C:8]1[CH:13]=[C:12]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[C:10]([Cl:15])[N:9]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1cc(N2CCCCC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of piperidine (0.910 g, 10.7 mmol) in 25 mL of THF and 5 mL of 1N NaOH was stirred for 30 minutes at 0° C., after which time 2,4,6-trichloropyridine (1.63 g, 8.86 mmol) was added. The reaction mixture was then stirred at 30-40° C. for 12-18 hours, after which the reaction mixture was cooled and neutralized with 5% HCl (aq). This product was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over 100-200 mesh silica gel by elution with 10:90 ethyl acetate: hexanes to afford the product as a pure colorless solid (yield 32%).
Reaction SMILES: [Si](Cl)(C)(C)C.BrCCBr.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].FC(F)(F)S(O[C:28]1[CH:37]=[CH:36][C:35]2[CH2:34][CH2:33][CH:32]([NH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:31]([CH2:44][C:45]3[CH:50]=[CH:49][C:48](Cl)=[C:47]([Cl:52])[CH:46]=3)[C:30]=2[CH:29]=1)(=O)=O>CC(N(C)C)=O.[Zn].[Cu]I.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].O>[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19]([C:28]2[CH:37]=[CH:36][C:35]3[CH2:34][CH2:33][CH:32]([NH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:31]([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([Cl:52])[CH:46]=4)[C:30]=3[CH:29]=2)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Solvent: O
Product: CCOC(=O)NC1CCc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2C1Cc1cccc(Cl)c1
Temperature: 67.5 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
A suspension of zinc powder (152 mg, 2.3 mmol) in 1 ml of DMA in a dry flask was heated under N2 to 65-70° C. A mixture of TMS-Cl (28 mg, 0.26 mmol) and 1,2-dibromoethane (49 mg, 0.26 mmol) was added dropwise, stirred for 30 min, followed by slow (15 min) addition of 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (510 mg, 1.8 mmol) in 1 ml DMA. The reaction was cooled slowly (3 h) to room temperature, added to a mixture of 8-(3,4-chlorobenzyl)-7-[(ethoxycarbonyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (633 mg, 1.3 mmol, prepared in analogy to example 29), CuI (74 mg, 0.39 mmol) and PdCl2(dppf) (63 mg, 0.08 mmol) in 4 ml DMA preheated to 70° C. and stirred for 7 h at 70° C. Water and MTB (1:1 20 ml) were added and the resulting mixture filtered. The organic layer was separated, dried (Na2SO4) and the solvent evaporated. Purification by chromatography afforded 560 mg of product (white foam).