Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=O)[C:6]=2[O:5][CH2:4][C:3]1=[O:15].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[C:19]([Cl:25])[CH:18]=1>[Zn].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>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:12]([C:11]2[C:6]3[O:5][CH2:4][C:3](=[O:15])[N:2]([CH3:1])[C:7]=3[CH:8]=[CH:9][CH:10]=2)=[O:14])=[C:19]([Cl:25])[CH:18]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: CN1C(=O)COc2c(C(=O)O)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Product: CN1C(=O)COc2c(C(=O)Cc3ccc(Br)cc3Cl)cccc21

Procedure:
In analogy to Example 49, step 1, 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid (CAS Reg. No. 1017273-27-6) was converted to the acid chloride and subsequently reacted with 4-bromo-1-bromomethyl-2-chloro-benzene in the presence of zinc and tetrakis(triphenylphosphine)palladium(0) to give the title compound as a colorless solid. MS (m/e, ISP neg. ion)=392.1 [M−H+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1.C(N(CC)CC)C.C1C=CC(O[C:44](OC2C=CC=CC=2)=[N:45][C:46]#[N:47])=CC=1.[CH3:55][NH2:56]>CC(O)C.CO>[C:55](/[N:47]=[C:46](/[NH:45][CH3:44])\[NH:1][CH2:2][CH2:3][CH2:4][C:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10]([N:12]([O:14][CH3:15])[CH3:13])=[O:11])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1)#[N:56]
Reactant: CN
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: CON(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Solvent: CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CN/C(=N/C#N)NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)N(C)OC
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (61 mg, 0.145 mmol, prepared as described in WO 2006/044825 Example 121) was weighed into a flask, then dissolved in 2.0 mL IPA. Triethylamine (0.051 ml, 0.362 mmol) was then added, followed by diphenyl cyanocarbonimidate (69 mg, 0.290 mmol). The reaction was stirred at 23° C. for 1.5 hours, then transferred to a pressure tube, followed by addition of 3 mL of methyl amine (2.4 ml, 4.9 mmol) in MeOH. The reaction was then placed in a 60° C. bath for 12 hours and then concentrated. The residue was purified by flash column chromatography (3-7% MeOH/DCM) affording the desired product (27 mg, 37%) as an orange foam film. MS ESI (+) m/z 502 (M+E) detected; 1H NMR (400 MHz, CDCl3) δ 7.52 (m, 1H), 7.46 (d, J=8.0H7-2H), 7.37 (m, 2H), 7.30 (m, 1H), 7.10 (m, 2H), 5.70 (m, 1h), 3.79 (s, 3H), 3.40 (m, 3H), 3.16 (m, 1H), 3.14 (s, 3H), 2.85 (s, 3H), 2.45 (m, 1H), 2.10 (m, 1H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CN(C1CCCCC1)C.Cl.[CH3:25][CH:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].[Cl:31][C:32]1[S:40][C:39]2[S:38](=[O:42])(=[O:41])[NH:37][C:36](=O)[NH:35][C:34]=2[CH:33]=1>O>[Cl:31][C:32]1[S:40][C:39]2[S:38](=[O:42])(=[O:41])[N:37]=[C:36]([NH:30][CH:26]([CH3:25])[CH:27]([CH3:29])[CH3:28])[NH:35][C:34]=2[CH:33]=1
Reactant: O=C1Nc2cc(Cl)sc2S(=O)(=O)N1
Reactant: CC(C)C(C)N
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: CN(C)C1CCCCC1
Product: CC(C)C(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 200 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
Phosphorus pentoxide (2.84 g; 20 mmol), N,N-dimethylcyclohexylamine (5 ml, 33 mmol) and 1,2-dimethylpropylamine hydrochloride (2.47 g; 20 mmol) were carefully mixed in a three necked flask equipped with mechanical stirring and condenser with drying tube. The mixture was heated on an oil bath at 200° C. until a homogeneous mass was obtained. Then 6-chloro-2,3-dihydro-3-oxo-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.2 g; 5 mmol) was added and the mixture was stirred at 240° C. for 45 min. The mixture was allowed to cool to about 100° C., 150 ml of water was added and stirring was continued at ambient temperature for approximately 1 h. The hydrolysed mixture was filtered and the dark precipitate was washed with water and dissolved in boiling ethanol, treated with charcoal, filtered and finally evaporated to dryness. Flash chromatography (ethyl acetate/silica gel) afforded 105 mg (7%) of the pure title compound; m.p. 216°-218° C.; 1H-NMR (DMSO-d6): δ 0.90 (d, 6H, CH(CH3)2), 1.08 (d, 3H, NCHCH3), 1.75 (m, 1H, CH(CH3)2), 3.65 (m, 1H, NHCH), 7.11 (br. s, 2H, 5-H+NH), 10.68 (s, 1H, NH); MS m/e: 307/309 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH:22]=O>CO>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[CH2:22][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Product: C[C@H](NCc1cc(Cl)cc(Cl)c1)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
Borane-pyridine complex (130 μL, 1.21 mmol) was added to an methanol solution (4 mL) of an amine (3) (105 mg, 0.40 mmol) and 3,5-dichlorobenzaldehyde (95 mg, 0.52 mmol) at 40° C. and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol-10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (6) as a white solid (76 mg, yield 45%).
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[OH:18])(=[O:7])=[O:6])[CH2:2][CH3:3].[H][H]>[Pd]>[CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:18])(=[O:7])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 96.2 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-propyl-6chloro-2-hydroxy-3-nitrobenzenesulfonamide (650 mg, 2.2 mmol) was reduced with hydrogen and 10% Pd/C (320 mg) to form the desired product (560 mg, 96%). 1H NMR (MeOD-d4): δ 6.83 (m, 1H), 2.86 (t, 2H), 1.50 (m, 2H), 0.87 (t, 3H).
Reaction SMILES: [C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=N)#[N:2].Cl.[OH2:25]>>[C:1]([CH:3]1[C:12]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[C:11]2[C:6](=[C:7]3[CH:22]=[CH:21][N:20]=[C:8]3[CH:9]=[CH:10]2)[O:5][C:4]1=[O:25])#[N:2]
Reactant: Cc1cncc(C2=c3ccc4c(c3OC(=N)C2C#N)C=CN=4)c1
Reactant: O
Agent: Cl
Product: Cc1cncc(C2=c3ccc4c(c3OC(=O)C2C#N)C=CN=4)c1

Procedure:
The process further comprises contacting the 2-iminobenzopyran with an aqueous acid to produce an optionally substituted coumarin (2-oxo-2H-chromene). For example, the hydrolysis of 3-cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene using HCl/H2O produced 3-cyano-4-(5-methyl-pyridin-3-yl)-2-oxo-2H-pyrrolo[2,3-h]chromene (compound of Formula III).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.N12CCCN=C1CCCCC2.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCCl.C(Cl)(Cl)Cl>[CH:9]1([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([N+:14]([O-:16])=[O:15])=[CH:3][C:2]=3[NH:1][C:29]2=[O:31])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1NC1CCCC1
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]c2cc([N+](=O)[O-])ccc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83.7 %

Procedure:
To a solution of 3-amino-4-cyclopentylamino-1-nitrobenzene (445 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) in 1,2-dichloroethane (5 mL) was added triphosgene (358 mg) at 0° C., and the mixture was stirred at room temperature under nitrogen atmosphere for 20 minutes. The resulting mixture was diluted with chloroform and washed successively with water(twice) and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (3:1). The obtained substance was triturated with diisopropyl ether to give 1-cyclopentyl-5-nitro-2,3-dihydro-1H-benzimidazol-2-one (249.8 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CO.[BH4-].[Na+]>O>[CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OC1CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A 100-mL round-bottom flask was charged with 3-(benzyloxy)cyclobutanone (2.00 g, 11.4 mmol), tetrahydrofuran (20 mL), and methanol (1 mL), and the solution was cooled to 0° C. Sodium borohydride (0.475 g, 12.5 mmol) was added portionwise, and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was poured into water (30 mL), and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-(benzyloxy)cyclobutanol (1.83 g, 90%) as yellow oil. MS (ESI, pos. ion) m/z 179 [M+H]+.
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][CH2:31][C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C:38]#[C:39][C:40](=[O:42])[CH3:41])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.O>ClCCl>[O:42]=[C:40]([CH3:41])[C:39]#[C:38][C@H:28]1[CH2:27][CH2:26][C@H:25]2[C@H:24]3[C@H:33]([CH2:32][CH2:31][C@:29]12[CH3:30])[C@:34]1([CH3:37])[C@H:21]([CH2:20][C@H:19]([OH:18])[CH2:36][CH2:35]1)[CH2:22][CH2:23]3
Reactant: CC(=O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4[3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-yl]-3-butyn-2-one (40 mg, 0.07 mmol) in anhydrous dichloromethane (2.8 mL) was treated with HF pyridine (0.008 mL, 0.28 mmol) at 0° C. and the resulting mixture was stirred at RT for 2 h. Addition of water at 0° C. was followed by extraction with methylene chloride. The organic layer was washed with brine and was dried with Na2SO4 and the solvent was evaporated in vacuo. Subsequent purification of the residue with flash column chromatography using dichloromethane/ethyl acetate 95/5 as eluent afforded the desired compound named above.
Reaction SMILES: Br[CH:2]([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.COC1C=C2C(=CC=1OC)CNC2.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[CH2:48][NH:47][CH2:46][CH2:45]2>>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:26][N:47]2[CH2:46][CH2:45][C:44]3[C:49](=[C:50]([O:54][CH3:55])[C:51]([O:52][CH3:53])=[C:42]([O:41][CH3:40])[CH:43]=3)[CH2:48]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(CCCCC(C)Br)Sc2ccc(C)cc2)cc1OC
Reactant: COc1cc2c(c(OC)c1OC)CNCC2
Agent: COc1cc2c(cc1OC)CNC2
Product: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)c(OC)c3C2)Sc2ccc(C)cc2)cc1OC
Yield: 65.7 %

Procedure:
The procedure of Example 49 is repeated using 5.31 g 4-[6-bromo-1-[(4-methylphenyl)thio]heptyl]-1,2-dimethoxybenzene, 3.29 g of 5,6-dimethoxyisoindoline and 2.65 g of 6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline. This affords 4.52 g of the desired product as a yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([O:16][CH3:17])=[O:15]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[CH:13][N:9]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CCCN1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(Br)ccn1C(=O)OC(C)(C)C
Temperature: 85 °C
Yield: 40 %

Procedure:
Synthesis was carried out according to the procedure reported: Hasse et al., Aust. J. Chem., 62(7):683-691 (2009). Crystallized (from water) N-bromo succinimide (100 g, 564 mmol) was added to a solution of 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate (34.0 g, 148 mmol) in carbon tetrachloride (17 L). The resulting suspension was heated at 85° C. for 2 h. The reaction mixture was cooled to 0° C. and the precipitated succinimide removed by filtration. The filtrate was concentrated under reduced pressure. The dark orange oil obtained was subjected to column chromatography (REDISEP®, silica gel, 120 g, 10% EtOAc/hexanes), gave 1-tert-butyl 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate (18.0 g, 39.1%) as an orange color liquid. 1H NMR (400 MHz, CD3OD) 6 ppm: 1.53 (s, 9H), 3.32 (s, 3H), 6.46 (d, J=3.6 Hz, 1H), 7.44 (d, J=3.6 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=CCCCCc1ccccc1
Yield: 48.6 %

Procedure:
t-butyl 7-phenylhept-2-enoate (19 g; 70 mmol) is dissolved in dry CH2Cl2 (120 mL) and trifluoroacetic acid (25 mL) is added slowly. After 5 hours the reaction is concentrated in vacuo and purified by column chromatography using CH2Cl2 to obtain 7-phenylhept-2-enoic acid (7 g; 34 mmol). 1H NMR (300 MHz, CDCl3) δ 12-10 (br, 1H), 7.30-7.24 (m, 2H), 7.20-7.12 (m, 3H), 7.06 (dd, J=15.7, 7 Hz, 1H), 5.80 (d, J=15.7 Hz, 1H), 2.62 (t, J=7.5 HZ, 2H), 2.25 (q, J=7 HZ, 2H), 1.70-1.61 (m, 2H), 1.56-1.46 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](O)([CH3:12])[CH3:11].CCOC(C)=O>CCO.[Pd]>[CH:10]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH2:1])([CH3:12])[CH3:11]
Reactant: COc1ccc(C(C)(C)O)c(N)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)c(N)c1
Yield: 80.7 %

Procedure:
To a solution of 2-(2-amino-4-methoxyphenyl)propan-2-ol (210 mg; 1.2 mmol; 1 eq) in a mixture of EtOH (10 mL), EtOAc (3 mL) and 5 N (1 mL) under nitrogen atmosphere is added palladium on charcoal (130 mg; 10%) and the reaction mixture is hydrogenated for 1 week at room temperature at 1 atmosphere. The catalyst is filtered through celite and the organic solvents are removed under vacuum. The residue is taken up in EtOAc. The organic phase is washed with a saturated aqueous solution of Na2CO3 and dried over MgSO4. The solvent is evaporated under reduced pressure to afford 160 mg (84%) of the title compound as a red oil. The compound is used in the next step without further purification. 1H NMR (DMSO-d6) δ 6.89 (d, J=9.0 Hz, 1H), 6.18 (d, J=3.0 Hz, 1H), 6.05 (dd, J=9.0, 3.0 Hz, 1H), 5.45-5.39 (m, 2H), 3.85 (s, 3H), 3.30-3.11 (m, 1H), 1.97 (s, 6H). HPLC (max plot) 70%; Rt 1.88 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.[ClH:61].[N:62]1([CH2:67][C:68](O)=[O:69])[CH:66]=[CH:65][N:64]=[CH:63]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:61].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([O:21][C:68](=[O:69])[CH2:67][N:62]2[CH:66]=[CH:65][N:64]=[CH:63]2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reactant: O=C(O)Cn1ccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)Cn2ccnc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A suspension comprising 422 mg (0.80 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12), 311 mg (1.51 mmol) of dicyclohexylcarbodiimide, 142 μl (1.76 mmol) of pyridine, 20 mg (0.16 mmol) of 4-(N,N-dimethylamino)pyridine and 156 mg (0.96 mmol) of 2-(1-imidazolyl)acetic acid hydrochloride in 10 ml of methylene chloride was stirred for 3 days. At the end of this time, insoluble materials were filtered off, and the filtrate was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 75 g of silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give 507 mg (a quantitative yield) of the title compound as a colorless foam-like material.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][C:49](O)=[O:50])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[O:50]=[C:49]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:48][CH2:47][NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.4 %

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (5.9 g, 15.4 mmol), pyrrolidine (3.2 g, 16.8 mmol) and diisopropylethylamine (5.4 mL, 42.2 mmol) was added to a suspension of 3-((tert-butoxycarbonyl)amino)propanoic acid (1.0 g, 14.0 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at ambient temperature for 6 hours. TLC analysis showed no acid remaining so the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvent was removed to afford a solid. The crude material was purified by silica gel chromatography using a 70:30 mixture of hexane and ethyl acetate as eluent to afford the title product as a solid (3.0 g, 88% yield). MS m/z: 243.26 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH3:19])[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1.B1([C:26]2[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=2)OCCCO1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:19][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:9]=1
Reactant: c1cncc(B2OCCCO2)c1
Reactant: Cc1cncc(Cl)c1-c1nc(-c2ccccn2)no1
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: ClCCl
Solvent: COCCOC
Product: Cc1cncc(-c2cccnc2)c1-c1nc(-c2ccccn2)no1

Procedure:
A mixture of 5-(3-chloro-5-methyl-pyrid-4-yl)-3-(2-pyridyl)-1,2,4-oxadiazole (75 mg, 0.275 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (75 mg, 0.46 mmol), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 30 mg, 0.026 mmol), in a solution of ethylene glycol dimethyl ether (1 mL) and 2M sodium carbonate (1 mL) was heated in a sealed vial at 100° C. for 1 hour. The reaction was cooled, diluted with dichloromethane, washed with water and saturated brine, filtered, and concentrated. Silica gel chromatography using a gradient of 40% ethyl acetate in hexane to 100% ethyl acetate afforded 5.4 mg (7.4%) of 5-[3-methyl-5-(3-pyridyl)-pyrid-4-yl]-3-(2-pyridyl)-1,2,4-oxadiazble. 1H-NMR (CDCl3), δ (ppm): 9.32 (s, 1H), 8.87 (d, 1H), 8.70 (d, 1H), 8.30 (m, 2H), 8.25 (s, 1H), 8.00 (s, 1H), 7.90 (d, 1H), 7.47 (m, 2H), 2.77 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26].O>CN(C=O)C>[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[N:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8]1.[F:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:8]1[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[N:7]1
Reactant: CCOC(=O)c1nc(-c2nccs2)n[nH]1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Product: CCOC(=O)c1nc(-c2nccs2)nn1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %
Yield: 48 %

Procedure:
To a solution of ethyl 3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate (Intermediate-2, 1.7 mmol) in DMF (8 mL) was added sodium hydride (1.2 equiv). After 10 min, 1-(bromomethyl)-2-fluorobenzene (1.2 equiv) was added. The reaction was stirred at ambient temperature for 35 min. The reaction mixture was poured into water and extracted with EtOAc. The organic phases were washed with water and brine, dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate solvent gradient (EtOAc/hexanes) to give ethyl 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboxylate (48%) and ethyl 1-(2-fluorobenzyl)-3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate as white solids (44% yield).
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)=[C:3]([Cl:5])[Cl:4].O[CH2:14][NH:15][C:16](=[O:19])[CH2:17][Cl:18].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Cl:18][CH2:17][C:16]([NH:15][CH2:14][C:9]1[CH:10]=[CH:11][C:6]([C:2]([Cl:1])=[C:3]([Cl:4])[Cl:5])=[CH:7][C:8]=1[OH:12])=[O:19]
Reactant: O=C(CCl)NCO
Reactant: Oc1cccc(C(Cl)=C(Cl)Cl)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CCl)NCc1ccc(C(Cl)=C(Cl)Cl)cc1O
Temperature: 25 °C

Procedure:
A mixture of 2.02 g (9.0 mmol) of the product of Step D and 1.10 g (9.0 mmol) of N-hydroxymethyl-2-chloroacetamide was added in portions to a vigorously stirred solution of 9.0 mL acetic acid and 1.0 mL (98%) sulfuric acid at 0-10° C. The reaction mixture was allowed to warm to room temperature over several hours, and stirring was maintained for a total of 2 days. The reaction mixture was poured into ice-water, neutralized with saturated aqueous NaHCO3 solution and extracted into CH2Cl2. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with a gradient of 10-30% EtOAc in hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.