Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[C:4]([CH:11]=[O:12])[CH:3]=1.CS(C)=O.[F:17][C:18]([F:27])([F:26])/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C(OCC)C.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:10][CH:19]([C:18]([F:17])([F:27])[F:26])[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:7][C:6]=2[CH:9]=1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(Cl)cc(C=O)c1O
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Temperature: 80 °C
Yield: 35.3 %

Procedure:
A stirred solution of the dialdehyde (Step 2) (1.13 g, 6.14 mmol), dimethyl sulfoxide (6 mL), ethyl 4,4,4-trifluorocrotonate (1.37 mL, 1.55 g, 9.21 mmoL) and triethylamine (1.71 mL, 1.24 g, 12.28 mmol) in a round bottom flask fitted with condenser was heated to 80° C. for 8 h. Upon cooling to room temperature the reaction was diluted with diethyl ether (100 mL) and the resulting mixture washed with aqueous sodium bicarbonate solution (3×75 mL), 1 N HCl solution (3×70 mL), and brine (1×75 mL), dried over MgSO4, filtered and concentrated in vacuo yielding a tan powder. This powder was taken up in hot hexane-ethyl acetate and filtered to remove insoluble matter. Upon cooling of the filtrate, crystallization followed by vacuum filtration yielded the desired ester as tan crystals (0.726 g, 35%): mp 118.1–119.7° C. This material was of suitable purity to use without further purification.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[C:4]1[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:5]=1[NH:6]2.Cl.N([O-])=O.[Na+].[I:23]I.[I-].[K+]>CC(O)=O.O>[I:23][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[C:7]2[C:3]=1[C:4]1[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:5]=1[NH:6]2
Reactant: Cc1cnc2[nH]c3cc(C#N)cc(N)c3c2c1
Reactant: II
Agent: Cl
Agent: O=N[O-]
Agent: [I-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc2[nH]c3cc(C#N)cc(I)c3c2c1
Temperature: 0 °C
Yield: 822.8 %

Procedure:
Compound 124 (118 mg, 0.53 mmol) was dissolved in HOAc (2 mL) with H2O (1 mL), and the solution stirred at 0° C. Concentrated HCl (120 μL) in H2O (120 mL) was added, and the reaction stirred for 5 min. Sodium nitrite (54 mg, 0.78 mmol) in H2O (120 μL) was added dropwise, and the red solution stirred for 10 min. A solution of iodine (10 mg) and potassium iodide (129 mg, 0.78 mmol) in H2O (300 μL) was added dropwise, and the brown frothy solution stirred for 30 min at 0° C. and then 30 min while warming to r.t. The reaction was diluted with H2O (5 mL) and extracted with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography gave 108 mg (61%) of the title compound as a faintly yellow solid. MS (ES) [m+H] calc'd for C13H8IN3, 334; found 334.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[C:3]=1[C:15]#[N:16].C(N(CC)CC)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:15]([C:3]1[C:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[S:6][C:5]=2[CH:13]=[CH:14][C:2]=1[NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])#[N:16]
Reactant: N#Cc1c(N)ccc2sc3ccccc3c12
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1C#N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-amino-1-cyanodibenzothiophene (J. Heterocyclyl. Chem., 1977, 14(7), 1209-1214; 0.043 g, 0.19 mmol), triethylamine (0.04 g, 0.4 mmol) and pivaloyl chloride (0.05 g, 0.4 mmol) in DCM (2 ml) was stirred at ambient temperature for 24 hours. The resultant mixture was extracted with water and the organic phase reduced to a residue which was triturated with ether/iso-hexane to give the title compound. NMR: 9.78 (s, 1H), 8.81 (m, 1H), 8.38 (d, 1H), 8.16 (m, 1H), 7.58 (m, 2H), 7.48 (d, 1H), 1.18 (s, 9H); m/z 307 (M−H)−.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:5]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:16][CH:17]=3)[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:3]1[C:4]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:5]2[CH:11]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:16][CH2:17]3)[NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(C3=CCN(CC(=O)N(C)C)CC3)cc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(C3CCN(CC(=O)N(C)C)CC3)cc12

Procedure:
A solution of Example 236G (80 mg, 0.185 mmol) in methanol (10 mL) was added to 20% palladium hydroxide on carbon (wet) (40 mg, 0.029 mmol) in a pressure bottle. The mixture was stirred at 50° C. under 30 psi hydrogen for 16 hours and filtered. The filtrate was concentrated and the residue was purified by reverse-phase HPLC on a Phenomenex Luna C8 AXIA column (100 Å) using a gradient of 10-95% acetonitrile/0.1% trifluoroacetic acid in water to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 2.00-2.20 (m, 2H), 2.21-2.30 (m, 2H), 2.90-2.98 (m, 6H), 2.98-3.45 (m, 5H), 3.75 (s, 3H), 4.21 (s, 2H), 6.09 (bs, 1H), 7.20 (dd, J=8.6, 3.1 Hz, 1H), 7.26 (dd, J=9.1, 4.5 Hz, 1H), 7.29-7.38 (m, 1H), 8.54 (s, 1H), 12.12 (bs, 1H). MS (ESI(+)) m/e 436 (M+H)+
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[N:17]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]=3[N:16]=2)=[N:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.C([Mg]Cl)(C)C>C(Cl)Cl>[CH3:23][N:21]([CH3:22])[C:20]([C:18]1[N:17]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:15]2[N:16]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([N:31]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]4)=[O:30])=[CH:5][N:6]=3)[N:12]=[CH:13][C:14]=2[CH:19]=1)=[O:24]
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC(O)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
To a solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (200 mg, 0.49 mmol) and piperidin-4-ol (500 mg, 4.9 mmol) in 5 mL of CH2Cl2 is added dropwise a solution of iPrMgCl (2.45 mL, 4.9 mmol) at 0° C. and allow to warm up to room temperature overnight. After 18 h, added another 10 equivalents of i-PrMgCl and stirred for another 5 h. The reaction mixture is quenched with saturated NH4Cl and extracted with dichloromethane (3×100 mL). The combine organic ished with NaCl and dried over Na2SO4 and concentrated. Following SiO2 chromatography, eluting with 85/15% (CH2Cl2/MeOH) gave 7-cyclopentyl-2-[5-(4-hydroxy-piperidine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (120 mg, 51%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH3:21])=[N:15][C:16]=2Cl.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:19]=[N:18][C:17]2[C:12]1=[N:13][C:14]([CH3:21])=[N:15][C:16]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: Cc1nc(Cl)c2ncn(-c3ccc(C(C)C)cc3Br)c2n1
Reactant: C1COCCN1
Product: Cc1nc(N2CCOCC2)c2ncn(-c3ccc(C(C)C)cc3Br)c2n1

Procedure:
9[2-bromo-4(2-propyl)phenyl]-2-methyl-6-chloropurine (1.3 g) and morpholine (10 mL) were combined under nitrogen and refluxed for 6 hrs. The reaction mixture was concentrated by rotovap and the residue was purified by flash chromatography (CH2C2:MeOH, 50:1; silica) to yield a yellow solid (0.54 g). MS (M+H)+416, 418.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6](=O)[C:7]([OH:9])=[O:8])[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]1=2.Cl.[CH2:16]([O:23][NH2:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+].[N+](=C)=[N-].Cl>C(O)C.O.CCOCC.CO>[CH2:16]([O:23][N:24]=[C:6]([C:4]1[C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[S:1][CH:5]=1)[C:7]([OH:9])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)C(=O)c1csc2ccccc12
Agent: C=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: O=C(O)C(=NOCc1ccccc1)c1csc2ccccc12
Reaction time: 2 h
Yield: 37.6 %

Procedure:
Benzo[b]-thien-3-ylglyoxylic acid (2.27 g) and benzyloxyamine hydrochloride (1.915 g) were dissolved in ethanol (70 ml) and water (30 ml). The solution was adjusted to pH 4.5 with 40% w/v sodium hydroxide solution and stirred at this pH for 2 hr. The solution was stood overnight and adjusted to pH 9 then washed with ether. The aqueous phase was acidified under ethyl acetate and the organic layer was washed with water, saturated brine and dried. Evaporation gave a mixture of syn and anti-isomers as a buff crystalline solid (3.4 g., 99%). The crude acid in ether was treated with excess diazomethane in ether at 0°-5°. The excess reagent was destroyed with acetic acid and the ether solution was washed with sodium bicarbonate, water and dried. Evaporation gave a pale brown oil (3.34 g., 93%). The crude product in methanol (100 ml.) was treated with sodium hydroxide solution (1N, 10 ml) at room temperature for 1 hr. The hydrolysis was followed by thin layer chromatography on silica. Hydrochloric acid (2N 5 ml.) was added to stop the hydrolysis and methanol was removed by evaporation. Ethyl acetate was added and the anti-2-benzyloxyimino-2-(benzo[b]-thien-3-yl)acetic acid was removed by washing with sodium bicarbonate. The ethyl acetate layer was washed with water and dried and evaporated to a pale orange oil (1.99 g., 56%). This was treated in methanol (90 ml.) with sodium hydroxide (1N; 10 ml) at room temperature for 7 hr. A further aliquot of sodium hydroxide (1N; 5 ml) was added and the solution stood for 2 days to complete hydrolysis. The methanol was removed by evaporation and the residue dissolved in ethyl acetate and water. The mixture was adjusted to pH 1.5 and the ethyl acetate layer was washed with water, saturated brine and dried. Evaporation gave yellow crystals (1.82 g. 50%) Crystallisation from a mixture of benzene and cyclohexane gave the title compound as pale orange crystals (1.29 g., 36%), m.p. 120.5°-121°, λmax. (EtOH) 232, 285.5, 296.5 306.5 nm. (ε22,500, 11,800, 11,500, 10,400), τ values (DMSO-d6) include 1.90, 1.97, 2.3-2.7 (aromatic protons), 4.64 (CH2 singlet).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[ClH:5].[CH:6]1([CH2:9][N:10]2[CH2:27][CH2:26][C@@:17]34[C:18]5[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=5[CH2:24][C@@H:11]2[C@:12]3([O:30][CH3:31])[C@H:13]([CH3:29])[CH2:14][C:15](=[O:28])[CH2:16]4)[CH2:8][CH2:7]1>CO>[ClH:5].[CH:6]1([CH2:9][N:10]2[CH2:27][CH2:26][C@@:17]34[C:18]5[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=5[CH2:24][C@@H:11]2[C@:12]3([O:30][CH3:31])[C@H:13]([CH3:29])[CH2:14][CH:15]([OH:28])[CH2:16]4)[CH2:7][CH2:8]1
Reactant: CO[C@@]12[C@H](C)CC(=O)C[C@@]13CCN(CC1CC1)[C@@H]2Cc1ccc(O)cc13
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@@]12[C@H](C)CC(O)C[C@@]13CCN(CC1CC1)[C@@H]2Cc1ccc(O)cc13
Reaction time: 4 h

Procedure:
Sodium borohydride (0.38 g, 10.04 mmol) was added to a 3-necked flask fitted with a dropping funnel and a condensor. Under a nitrogen atmosphere, a solution of 20 mg of NaOH in 10 ml of methanol was added to the flask and the mixture stirred while a solution of 17-cyclopropylmethyl-3-hydroxy-14-methoxy-8α-methylmorphinan-6-one (31) (0.188 g, 0.528 mmol) in 10 ml of methanol was added dropwise. At this point the reaction mixture was stirred for four hrs. whereupon the reaction was quenched by the addition of 8 ml of 2 N HCl and heating in an oil bath for 10 minutes. The solvent was removed under reduced pressure, then 15 ml of methanol and 10 ml of water were added and the methanol removed under reduced pressure. This step was repeated whereupon the aqueous solution was made basic with solid Na2CO3. A white precipitate formed which was filtered off and the filtrate was extracted with chloroform (4×20 ml). The organic layer was separated, dried over Na2SO4 and concentrated to leave a gummy residue. The residue was chromatographed on silica gel and eluted with methanol:chloroform (50:50) containing a drop of NH4OH to give the free base of (34) upon evaporation of the solvent. The free base was dissolved in chloroform and treated with ethereal HCl to give 17-cyclopropylmethyl-14-methoxy-8α-methylmorphinan-3,6-diol hydrochloride (34) as a colorless solid (0.1 g, 48% theory).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20].[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>CCO>[OH:33][C@H:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[C:3]([C:19]#[N:20])[CH:4]=3)[N:9]=2)[C:13](=[O:18])[CH2:14]1
Reactant: Cc1cc2nc(N3CCNCC3=O)ccc2cc1C#N
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1cc2nc(N3CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3=O)ccc2cc1C#N
Temperature: 140 °C

Procedure:
A mixture of 7-Methyl-2-(2-oxopiperazin-1-yl)quinoline-6-carbonitrile [I-3] (125 mg, 0.47 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (134 mg, 0.70 mmol) in EtOH (1.5 mL) in a 5 mL microwave tube was heated to 140° C. for 20 minutes. LC showed formation of the desired product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1>CN(C)C=O.O1CCOCC1.C(N(CC)CC)C>[Cl:18][C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Clc1cnc(N2CCC3(CC2)OCCO3)nc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (2.39 g) is combined with 2,5-dichloropyrimidine (2.44 g) in N,N-dimethylformamide (50 mL), 1,4-dioxane (75 mL) and triethylamine (6.7 mL) in a glass pressure reaction vessel and heated with stirring at 120° C. for 16 h. After cooling the orange solution is concentrated and partitioned between dichloromethane (100 mL) and water (100 mL). The water layer is extracted with dichloromethane (100 mL). The dichloromethane layers are combined, washed with water (2×100 mL), dried over Na2SO4, filtered and concentrated to give the title compound. LC (method 20): tR=2.24 min; Mass spectrum (APCI): m/z=256 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)=[CH:6][C:3]=1[CH2:4][OH:5]>ClCCl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(-c2cc(C)c(N)c(CO)c2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(-c2cc(C)c(N)c(C=O)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Freshly dried manganese dioxide (1.5 g) was added to a solution of 2-amino-5-(2-methoxypyrid-5-yl)-3-methylbenzyl alcohol (1.5 g) in dichloromethane (20 cm3) under nitrogen and the mixture was stirred for 2 hours at room temperature. The mixture was filtered, the filtrate evaporated to dryness, and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark])eluting with dichloromethane. Combination and evaporation of appropriate fractions afforded the title compound, m.p. 81°-84° (0.98 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1.Br[C:14]1[S:18][C:17]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:22]([CH3:33])[CH2:21]2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(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>[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]2[S:18][C:17]([CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@@H:22]([CH3:33])[CH2:21]3)=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: NCc1cccc(B(O)O)c1
Reactant: C[C@H]1CN(Cc2ccc(Br)s2)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2ccc(-c3cccc(CN)c3)s2)CCN1C(=O)OC(C)(C)C
Yield: 41.5 %

Procedure:
To the solution of [3-(aminomethyl)phenyl]boronic acid hydrochloride (325 mg, 1.2 mmol) in dioxane/H2O (10 mL/3.3 mL) was added 1,1-dimethylethyl (2S)-4-[(5-bromo-2-thienyl)methyl]-2-methyl-1-piperazinecarboxylate (450 mg, 1.2 mmol), K2CO3 (828 mg, 6.0 mmol) and Pd(PPh3)4 (70 mg, 0.06 mmol). The resulting solution was irradiated in a microwave reactor at 150° C. for 20 minutes and diluted with EtOAc (5 mL). The organic layer was collected and the aqueous layer was extracted by EtOAc (2×5 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by Gilson HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 90/10, v/v, over 12 min), to give the title compound (200 mg, 42%). LC/MS: m/z, 402 (M+H), 1.24 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+:20]([C:23]1[S:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1)([O-:22])=[O:21].OS(O)(=O)=O>CC(O)=O.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:28][C:26]2[S:27][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1C(=Cc2ccc([N+](=O)[O-])s2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 96 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with 5-nitrothiophene-2-carboxaldehyde (0.123 g, 0.78 mmol) in a mixture of HOAc (1 mL) and concentrated H2SO4 (0.100 mL) at room temperature overnight. The reaction was diluted with water, and the resulting precipitate was collected, washed well with water, and dried in vacuo at 60° C. to afford 0.296 g (80%) of the title compound as a brown powder, mp >240° C.: APCI-MS m/e 396.1 (M+ +1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[CH:20](N(C)C)[N:21]([CH3:23])[CH3:22])(C)(C)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[C:12](=[CH:20][N:21]([CH3:23])[CH3:22])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step A, 4.0 g, 20.0 mmol) in dimethylformamide (40 mL) was added tert-butoxybis(dimethylamino)methane (4.35 mL, 22 mmol). This mixture was stirred at reflux for 15 h, cooled to room temperature, diluted with water, and extracted with ethyl acetate (5×). The combined organic extracts were washed with water (3×) and brine (1×), dried over sodium sulfate, filtered, and evaporated to give 3.64 g (72%) of the title compound of Example 101, Step B as a brown oil that was sufficiently pure to carry on to the next step. 1H NMR (CDCl3, 400 MHz) δ 7.47 (s, 1H), 4.53 (s, 2H), 3.58 (t, 2H), 3.09 (s, 6H), 2.43 (t, 2H), 1.46 (s, 9H); MS (APCI) 255 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][CH2:11][Mg+].[Br-]>C1COCC1.O.Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC[Mg+]
Reactant: N#Cc1ccc(I)cn1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NC1(c2ccc(I)cn2)CC1
Reaction time: 23 h
Yield: 20.4 %

Procedure:
To a solution of 5-iodo-pyridine-2-carbonitrile (1.0 g, 8.1 mmol) in dry THF (50 mL) was added titanium(IV) isopropoxide (5.2 mL, 18 mmol). EtMgBr (3.0M in Et2O, 10 mL, 32 mmol) was then added dropwise. The reaction mixture was stirred for 23 h, then diluted with water (100 mL) and 1N HCl (5 mL), and stirred for 5 minutes. The mixture was filtered and the filtrate was concentrated in-vacuo to afford 430 mg of the title compound which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:7][CH2:8]O)=[CH:5][N:6]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][CH2:7][C:4]1[S:3][C:2]([NH2:1])=[N:6][CH:5]=1
Reactant: Nc1ncc(CCO)s1
Reactant: O=S(Cl)Cl
Product: Nc1ncc(CCCl)s1
Temperature: 62 °C

Procedure:
To a suspension of 2-(2-amino-thiazol-5-yl)-ethanol (0.844 g, 5.853 mmol) was added thionyl chloride (3 mL). The mixture was heated at 62° C. for 1 h. The volatiles were removed under reduced vacuum. The residue was co-evaporated with toluene (3×5 mL) to give 0.963 g of 5-(2-chloro-ethyl)-thiazol-2-ylamine crude 5-(2-chlorothyl)-2-thiazolamine monohydrochloride as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]([CH2:15][CH2:16]O)[CH2:12][CH2:13]O>>[Cl:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:16][CH2:15][NH:11][CH2:12][CH2:13][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: OB(O)c1cccc(Cl)c1
Product: Clc1cccc(B2OCCNCCO2)c1
Yield: 79 %

Procedure:
The title compound (79%, crystals) was prepared from 3-chlorophenylboronic acid and diethanolamin.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[C:17]([O:21][C:22](=[O:28])[NH:23][CH:24]1[CH2:27][NH:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:28])[NH:23][CH:24]1[CH2:27][N:26]([CH:5]2[CH2:6][CH2:7][C:2]([OH:1])([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([S:15][CH3:16])[CH:10]=3)[CH2:3][CH2:4]2)[CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CSc1cccc(C2(O)CCC(=O)CC2)c1
Product: CSc1cccc(C2(O)CCC(N3CC(NC(=O)OC(C)(C)C)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid from 4-hydroxy-4-(3-methylsulfanyl-phenyl)-cyclohexanone (as prepared in Example 14, Step B) and azetidin-3-yl-carbamic acid tert-butyl ester using the procedure described in Step D of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([S:12]([C:15]([F:20])([F:19])[CH:16]([Cl:18])[F:17])(=[O:14])=[O:13])=[CH:5]2.C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][C:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[S:12]([C:15]([F:20])([F:19])[CH:16]([Cl:18])[F:17])(=[O:13])=[O:14]
Reactant: BrBr
Reactant: O=S(=O)(c1cc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)C(F)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1[nH]c2cc(Cl)c(Cl)cc2c1Br)C(F)(F)C(F)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 5,6-dichloro-2[(2-chloro-1,1,2-trifluoroethyl)sulfonyl]indole (0.84 g, 2.29 mmole) and sodium acetate (0.21 g, 2.52 mmole in acetic acid is treated with bromine (0.40 g, 2.52 mmole), stirred for 0.5 hour at room temperature, poured onto water and filtered. The filtercake is air-dried to afford the title product as a white solid, 0.93 g (91% yield), mp 200°-205° C., identified by IR, 1HNMR and 19FNMR spectral analyses.