Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:8]=2[O:7][C:6]=1[CH3:23])=[O:4].Br[C:25]1[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31]2[C:32]([C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])=[N:33][O:34][C:35]=2[CH:36]2[CH2:38][CH2:37]2)=[CH:27][C:26]=1[CH3:49].N#N.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:25]3[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31]4[C:32]([C:39]5[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=5[Cl:46])=[N:33][O:34][C:35]=4[CH:36]4[CH2:38][CH2:37]4)=[CH:27][C:26]=3[CH3:49])=[CH:13][C:8]=2[O:7][C:6]=1[CH3:23])=[O:4]
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Reactant: COC(=O)c1c(C)oc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)oc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)cc3C)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
A solution of 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran-3-carboxylic acid methyl ester (0.145 g, 0.459 mmol) and 4-(4-bromo-3-methyl-phenoxymethyl)-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (229 mg, 0.504 mmol) in toluene (5 mL) is evacuated and refilled with N2 three times. Pd(OAc)2 (10 mg), 2-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl (38 mg) and potassium phosphate, tribasic, N-hydrate (195 mg) in water (0.5 mL) are added. The resulting mixture is evacuated and refilled with N2 three times and stirred at 110° C. for 16 hours. The mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated to a residue. The residue is purified via silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (0.14 g, 55%). 1H NMR (400 MHz, CDCl3): 7.90 (d, 1H), 7.39 (d, 1H), 7.37 (s, 1H), 7.31-7.29 (m, 2H), 7.18 (d, 1H), 7.10 (d, 1H), 6.70-6.66 (m, 2H), 4.80 (s, 2H), 3.94 (s, 3H), 2.76 (s, 3H), 2.18 (s, 3H), 2.17 (m, 1H), 1.29-1.25 (m, 2H), 1.15-1.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:23])[C:7]2=1.Cl.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29]Cl)[CH3:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([O:23][CH2:26][CH2:25][N:27]([CH2:31][CH3:32])[CH2:28][CH3:29])[C:7]2=1
Reactant: CCN(CC)CCCl
Reactant: Oc1cccc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Yield: 54.5 %

Procedure:
8-Chloro-9-(4-fluorobenzyl)-9H-carbazol-4-ol (0.1038 g, 0.32mmol), 2-diethylaminoethylchloride hydrochloride (0.0831 g, 0.48 mmol), potassium carbonate (0.1248 g, 0.90 mmol), sodium iodide (0.0037 g, 0.025 mmol) and DMF (1 mL) are heated at 85° C. for 5.5 h. After the mixture had cooled, it is partitioned between water and ether. The combined organic layers are dried over magnesium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (50 mL) using methanol/dichloromethane (1/99, 2/98 and 4/96) to give 0.0741 g (55%) of the title compound; mp 104.5-105.5° C.; MS (ESI+) for C25H26ClFN2O m/z 425.1 (M+H)+; IR (drift) 2966, 2932, 1590, 1506, 1455, 1414, 1354, 1334, 1270, 1221, 1157, 1124, 822, 791, 734 cm−1; 1H NMR (CDCl3) δ1.19, 2.82, 3.20, 4.43, 5.95, 6.73, 6.94, 7.04, 7.16, 7.36, 8.30. Anal. Calcd for C25H26ClFN2O: C, 70.66; H, 6.17; N, 6.59; Cl, 8.34. Found: C, 70.30; H, 6.13; N, 6.54.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@@H:4]1[O:23][C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([OH:25])=[CH:18][C:19]=2[OH:24])[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][C:8](=[O:9])[CH2:7][CH2:6][CH2:5]1>CO>[CH3:3][C@@H:4]1[O:23][C:21](=[O:22])[C:20]2[C:15](=[CH:16][C:17]([OH:25])=[CH:18][C:19]=2[OH:24])[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10][C@@H:8]([OH:9])[CH2:7][CH2:6][CH2:5]1
Reactant: C[C@H]1CCCC(=O)CCCC=Cc2cc(O)cc(O)c2C(=O)O1
Agent: C[C@H]1CCCC(=O)CCC/C=C\c2cc(O)cc(O)c2C(=O)O1
Agent: C[C@H]1CCC[C@H](O)CCC/C=C/c2cc(O)cc(O)c2C(=O)O1
Agent: [BH4-]
Solvent: CO
Product: C[C@H]1CCC[C@H](O)CCCC=Cc2cc(O)cc(O)c2C(=O)O1

Procedure:
Sodium borohydride (1 gram) is slowly added to 50 milliliters of methanol and 0.3 gram of cis-zearalenone while cooling the resultant reaction mixture. The mixture is then heated for 2 hours on a steam bath to evaporate the methanol. The residue is neutralized with HCl and extracted with two 40 milliliter portions of chloroform. The chloroform is then evaporated and the residue is purified by the column chromatography procedure of Example III, above, to yield about 0.28 gram of mixed diamers of cis-zearalenol.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[C:41]([C:40]1[CH:43]=[C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1
Temperature: 25 °C

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 200 mg, 0.448 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (206 mg, 0.896 mmol), Pd(PPh3)2Cl2 (31.5 mg, 0.045 mmol) and Na2CO3 (143 mg, 1.345 mmol) were added to a MW vial and treated with a mixture of DME (1.902 mL), water (543 μL) and EtOH (272 μL). The vial was sealed, evacuated/purged with argon and then the RM was subjected to MW irradiation at 120° C. for 10 min, then cooled to RT and finally treated with Si-Thiol (1.27 mmol/g, 176 mg, 0.224 mmol) overnight. The RM was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 14 min.) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.30 min, m/z=470.0-471.0 [M+H]+, m/z=468.0-469.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.27 (m, 2H) 3.34-3.44 (m, 1H) 4.17-4.24 (m, 1H) 4.70-5.04 (m, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:18].[CH2:19]=O>C(O)=O.O.[OH-].[Na+].C(O)C>[CH3:19][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C@@H:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:18]
Reactant: C=O
Reactant: O[C@@H]1Cc2ccccc2C[C@H]1CC1CCCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CCO
Solvent: O
Product: CN1CCCCC1C[C@@H]1Cc2ccccc2C[C@H]1O
Temperature: 0 °C

Procedure:
trans-1,2,3,4-Tetrahydro-3-(2-piperidinylmethyl)-2-naphthalenol from Part D (21.5 g, 0.088 M) is dissolved in 20 ml 35% formaldehyde solution and 50 ml 98% formic acid. The mixture is heated overnight on a steam bath. The solution is taken to near dryness in vacuo. The residue is dissolved in water and basified with 50% NaOH solution. The material is extracted into chloroform, dried and the solvent is removed leaving a brown oil which shows a strong peak in the carbonyl region on the IR. This is dissolved in ethanol, NaOH solution is added and the mixture is heated for a few minutes on a steam bath. After diluting with ice water the mixture is extracted twice with ether. The ether extracts are dried and the solvent is removed leaving 23 g (quant) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([C:14](O)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>C1COCC1.C1COCC1.O>[OH:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Temperature: -20 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2 g (8.7 mmol) of (1S,3R)-3-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid and 1.33 mL (9.6 mmol) of Et3N in 20 mL of anhydrous THF are added dropwise, at −20° C., 1.2 mL (9.2 mmol) of isobutyl chloroformate. The medium is stirred for 45 minutes at −20° C. and the insoluble material formed is then filtered off. A solution of 1 g (26.2 mmol) of sodium borohydride in a THF/H2O mixture (16 mL/4 mL) is added dropwise to the filtrate at −10° C. and stirring is then continued, while allowing the temperature to return to room temperature. 100 mL of 0.1N HCl are then added slowly and the reaction medium is then extracted with 2×200 mL of EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. After purification by chromatography on a column of silica gel, eluting with a DCM/MeOH mixture (95/5), 1.4 g of tert-butyl [(1R,3S)-3-(hydroxymethyl)cyclopentyl]carbamate are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH:13]([CH2:16][F:17])[CH2:14][F:15])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][C:3]=1[O:12][CH:13]([CH2:16][F:17])[CH2:14][F:15]
Reactant: COC(=O)c1cnc(OC(CF)CF)c(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cnc(OC(CF)CF)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
To a solution of methyl 5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]nicotinate (1 g) in THF (20 mL) was added dropwise a 0.99 M solution of DIBAL in toluene (11.3 mL) at 0° C., followed by stirring at 0° C. for 2 hours. Then, the reaction solution was poured into an aqueous Rochelle salt solution, followed by stirring at room temperature for 1 hour. After extraction with an EtOAc-water system, the organic layer was washed with brine, dried over MgSO4, and then filtered, and the desiccant was removed. The vehicle was evaporated under reduced pressure, followed by purification by silica gel column chromatography (Hex:AcOEt=98:2 to 70:30) to obtain {5-chloro-6-[(1,3-difluoropropan-2-yl)oxy]pyridin-3-yl}methanol (650 mg) as a colorless liquid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][CH:14]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[F:15].[I:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32]I>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:13][C:14]([P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:15])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][I:24]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: ICCOCCOCCI
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(F)(F)CCOCCOCCI
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (1.6 eq) in THF (1.28 M) was slowly added n-butyllithium (1.5 M in cyclohexane, 1.5 eq) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 minutes. The mixture was then cooled down to −78° C., and diethyl difluoromethylphosphonate (1 eq) in HMPA (2.1 M) was slowly added to the solution. Then the mixture was stirred at −78° C. for 40 minutes and to the resulting solution was added a cooled solution of 1,2-bis(2-iodoethoxy)ethane (12.8 M in THF, 4 eq) rapidly. After 1.5 hours, the reaction was quenched by pouring into saturated NH4Cl solution. The aqueous phases were extracted with ethyl acetate three times. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 10-100% EtOAc/Hex to give the product as a yellow oil.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[N:17]=[C:16]([CH:18]=[C:19]5[NH:24][C:22](=[CH:23][C:3](=[N:4]2)[CH2:2]1)[CH:21]=[CH:20]5)[CH2:15][CH2:14]4)=[CH:9][CH:8]=3.Br.IC1C=C(C=CC=1)CO.C([O-])([O-])=O.[K+].[K+]>>[CH2:9]1[C:10]2=[CH:12][C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:24]=[C:22]([CH:23]=[C:3]5[NH:4][C:5](=[CH:6][C:7](=[N:11]2)[CH2:8]1)[CH:1]=[CH:2]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3
Reactant: c1cc2cc3nc(cc4ccc(cc5nc(cc1[nH]2)CC5)[nH]4)CC3
Agent: Br
Agent: O=C([O-])[O-]
Agent: OCc1cccc(I)c1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)CC4)[nH]3

Procedure:
Bacteriohlorin 25: Following the procedure described for the synthesis of 16, treatment of 15 (50.0 mg, 0.0879 mmol, 1.0 equiv) with HBr gas, 3-iodobenzyl alcohol (0.1 mL), and K2CO3 (50.0 mg) resulted in the desired product. Purification was done by flash column chromatography (silica gel, 50% ethyl acetate in hexane). Yield: 42.8 mg, 62%. 1H NMR (400 MHz, CDCl3) δ: 8.52 (d, J=2.4 Hz, 1H, 10-H), 8.23 (s, 1H, 5-H), 8.05 (s, 1H, 20-H), 7.73 (d, J=21.6 Hz, 1H, Ph-H), 7.62 (d, J=7.6 Hz, 1H, Ph-H), 7.26 (1H, Ph-H, overlapping with the signal of CHCl3), 7.04 (t, J=8.0 Hz, 1H, Ph-H), 5.71 (q, J=6.4 Hz, 1H, 31-H), 4.97 (d, J=19.6 Hz, 1H, 132-H), 4.80 (d, J=19.6 Hz, 1H, 131-H), 4.46-4.63 (m, 2H, 31-OCH2), 4.11-4.19 (m, 2H, 7-H+18-H), 4.01 (d, 1H, 17-H), 3.88-3.90 (m, 1H, 8-H), 3.62 (s, 3H, COOCH3), 3.36 (s, 3H, 12-CH3), 3.15 (s, 3H, 2-CH3), 2.44-2.60 (m, 2H, 81-H+171-H), 2.11-2.34 (m, 3H, 171-CH2+171-H), 2.04 (d, J=6.4 Hz, 4H, 31-CH3+81-H), 1.65-1.77 (m, 6H, 7-CH3+18-CH3), 1.10-1.14 (m, 3H, 81-CH3), −0.22 (s, 1H, NH). MS (ESI) m/z: 785.4 (M++1). UV-vis, CH2Cl2, nm (ε): 720 (3.58×104), 659 (1.21×104), 602 (4.71×103), 517 (2.55×104), 486 (6.69×103), 456 (2.81×103), 382 (4.59×104), 353 (8.63×104).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:20][C:21]#[N:22])[CH2:16][C:15]4([CH2:19][CH2:18][CH2:17]4)[CH2:14]3)[CH:12]=2)[N:5]2[CH:23]=[CH:24][N:25]=[C:4]2[CH:3]=1.[O:26]1[CH2:29][CH:28]([N:30]2[CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=[N:31]2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:29][CH:28]([N:30]2[CH:34]=[C:33]([C:2]3[N:7]=[C:6]([C:8]4[CH:9]=[N:10][N:11]([C:13]5([CH2:20][C:21]#[N:22])[CH2:14][C:15]6([CH2:17][CH2:18][CH2:19]6)[CH2:16]5)[CH:12]=4)[N:5]4[CH:23]=[CH:24][N:25]=[C:4]4[CH:3]=3)[CH:32]=[N:31]2)[CH2:27]1
Reactant: CC1(C)OB(c2cnn(C3COC3)c2)OC1(C)C
Reactant: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CC2(CCC2)C1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3nc(-c4cnn(C5COC5)c4)cc4nccn34)cn2)CC2(CCC2)C1
Temperature: 80 °C
Yield: 73.7 %

Procedure:
2-(2-(4-(7-Chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.200 g, 0.567 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Table 2, compound f; 0.213 g, 0.850 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.054 g, 0.113 mmol) and K3PO4 (0.85 mL, 1.7 mmol) were suspended in 1,4-dioxane (10 mL) and purged with Ar (g). Pd2dba3 (0.052 g, 0.057 mmol) was added, and the system sealed and heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature and partitioned between saturated aqueous NaHCO3 and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2-3% (9:1 MeOH:NH4OH)/DCM to provide 2-(2-(4-(7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.184 g, 0.418 mmol, 74% yield). MS (apci) m/z=441.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[NH:23][CH:24]=[N:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2cc(F)ccc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2nc[nH]c12)c1nc2cc(F)ccc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 12.4 %

Procedure:
A mixture of (S)-1-(5-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 29 (379 mg, 1.4 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (340 mg, 1.4 mmol) and DIPEA (1.2 mL, 7.0 mmol) in n-butanol (7 mL) was stirred in a sealed vial for 18 h at 90° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 161 (65 mg, 12%). LCMS: RT 3.34 min [M+H]+ 374.1. 1H NMR (DMSO, 400 MHz): δ 8.19-8.00 (2H, m), 7.92 (1H, s), 7.67-7.41 (6H, m), 7.06 (2H, d, J=7.13 Hz), 5.47 (1H, s), 1.56 (3H, d, J=6.83 Hz)
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[CH:19][S:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[CH:19][S:18][C:13]3=2)[N:8]=1
Reactant: Oc1nc2ccc3ncsc3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2scnc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
Finely powdered potassium nitrate (92 mg, 0.9 mmol) was added to a stirred and ice-cooled solution of 7,8-dihydroxythiazolo[5,4-f]quinoxaline (0.20 g, 0.9 mmol) in 5 ml of conc. sulfuric acid. The mixture was stirred at 0° C. for 30 min, then at room temperature for 4 h, and finally poured into ice/water. The resulting precipitate was isolated by filtration, washed with water, and dried giving 0.15 g (62%) of the nitro compound; m.p.>360° C., IR (KBr): 1680 cm-1 ; 1H-NMR (DMSO-d6): 8.06 (s, 1H, ArH), 9.53 (s, 1H, ArH), 12.23 (broad s, 1H, OH), 12.76 (broad s, 1H, OH).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=C(C)C)[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)=[O:16].C(O)(C)C>C(OCC)(=O)C>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C:4](=[O:16])[CH:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C=O
Reactant: CCOC(=O)C1C(=C(C)C)CC[C@H]1C
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1C(=O)CC[C@H]1C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
(2R)-Ethyl 2-methyl-5-(propan-2-ylidene)cyclopentanecarboxylate (24 g, 0.122 mol) in ethyl acetate (100 mL) was cooled to −68° C. with dry ice/isopropanol. Ozonized oxygen (5-7 ft3h−1 of O2) was bubbled through the solution for 3.5 hours. The reaction mixture was flushed with nitrogen at room temperature until the color disappeared. The ethyl acetate was removed under vacuum, and the residue was dissolved in acetic acid (150 mL) and cooled by ice water. Zinc powder (45 g) was then added. The solution was stirred for 30 minutes and then filtered. The filtrate was neutralized with 2N NaOH (1.3 L) and NaHCO3. The aqueous phase was extracted with ether (3×200 mL). The organic phase was combined, washed with water, dried and concentrated to afford (2R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (20 g, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.21 (m, 2H), 2.77 (d, J=11.2 Hz, 1H), 2.60 (m, 1H), 2.50-2.10 (m, 3H), 1.42 (m, 1H), 1.33 (m, 3H), 1.23 (m, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)[N:13]=[CH:12][C:11]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH:33]([C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH2:36]1)=[O:34].C1(C)C=CC=CC=1>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.C(O)C>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[CH:33]=[O:34])=[CH:17][CH:16]=3)[N:13]=[CH:12][C:11]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=CC1(B(O)O)C=CC=CC1
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cc2)c1OCCN1CCOCC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(-c2ccc(-c3ccccc3C=O)cc2)c1OCCN1CCOCC1
Yield: 52.8 %

Procedure:
A mixture of ethyl 5-(2-morpholin-4-ylethoxy)-1-(4-bromophenyl)pyrazole-4-carboxylate (0.25 g, 0.59 mmol), sodium carbonate (0.20 g, 1.77 mmol), tetrakis(triphenylphosphine) palladium (0) (0.12 g, 0.18 mmol) and 1-formylbenzeneboronic acid (0.10 g, 0.76 mmol) in a solution of toluene (10 mL), ethanol (1 mL) and water (1 mL) was stirred at reflux for 18 h. The reaction was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine and dried (Na2SO4). After removing the solvent, flash chromatography of the residue (silica gel, 50% ethyl acetate/hexane) afforded the title compound as an oil (0.14 g, 66%). 1H NMR (250 MHz, CDCl3) d 9.98 (s, 1H), 8.01 (d, 1H), 7.92 (s, 1H), 7.85 (d, 2H), 7.62 (d, 1H), 7.46 (m, 4H), 4.65 (t, 2H), 4.35 (q, 2H), 3.56 (t, 4H), 2.68 (t, 2H), 2.38 (t, 4H), 1.38 (t, 3H). MS(ESI) m/e 450.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[OH-].[Na+].[CH3:17][N:18]=[C:19](SC)[S:20][CH3:21]>C(O)C>[CH3:17][NH:18][C:19](=[N:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[S:6][CH:7]=1)[S:20][CH3:21]
Reactant: CN=C(SC)SC
Reactant: CN(C)Cc1nc(CSCCN)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC(=NCCSCc1csc(CN(C)C)n1)SC

Procedure:
One g. of the oxalate salt of 2-dimethylaminomethyl-4-(2-aminoethyl)thiomethylthiazole was dissolved in 10 ml. of denatured ethanol and 4.8 ml. of 1N sodium hydroxide solution. To the mixture was added 0.36 g. of methylcarbonimidodithioic acid, dimethyl ester, and the reaction mixture was stirred under reflux for 16 hours. The mixture was then evaporated under vacuum, and the residue was taken up in 12 ml. of water and 1.5 ml. of 50% aqueous sodium hydroxide. The solution was extracted twice with 25 ml. portions of diethyl ether, and the organic layers were combined, dried over potassium carbonate and evaporated under vacuum to obtain 0.65 g. of the desired product in crude form. It was identified by nuclear magnetic resonance analysis as being identical to the product of Example 1.