Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]([CH3:23])(O[Si](C)(C)C)[C:14]([F:17])([F:16])[F:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:12][O:11][C:9]1[CH:10]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:13]([CH3:23])([C:14]([F:15])([F:16])[F:17])[O:24][C:3](=[O:2])[CH2:4]2
Reactant: COC(=O)Cc1cc(OC)ccc1C(C)(O[Si](C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(=O)OC2(C)C(F)(F)F
Reaction time: 1 h
Yield: 54 %

Procedure:
To the crude reaction mixture described in example 8 containing a solution of [5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-acetic acid methyl ester was added tetrabutylammonium fluoride (9.00 mL of a 1.0M solution in tetrahydrofuran, 9.00 mmol). The reaction mixture was stirred for 1 hour after which it was poured into water (50 mL) and extracted with methyl tert-butyl ether (50 mL). The organic layer was washed with water (50 mL) and brine (30 mL), dried over magnesium sulfate, filtered, and concentrated to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one as an oil (1.26 g, 54%). 1H NMR (400 MHz, CDCl3) δ1.89 (s, 3), 3.71 (d, 1, J=20.6), 3.79 (s, 3), 3.89 (d, 20.8), 6.65 (d, 1, J=1.5), 6.85-6.89 (m, 1), 7.29 (d, 1, J=8.7). 13C NMR (100 MHz, CDCl3) δ21.45, 34.32, 55.33, 83.01 (q, J=30.3), 112.21, 113.88, 120.57, 124.68 (q, J=285.7), 127.73, 132.18, 160.75, 167.45. IR 1765, 1614, 1509, 1322, 1301, 1274, 1259, 1183, 1101, 997, 813 cm−1. Analysis calculated for C12H11F3O3: C, 55.39; H, 4.26. Found: C, 55.03; H, 4.54.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]([CH3:41])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:31]4[C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:28]([N:27]([CH3:41])[CH3:26])=[CH:29][CH:30]=4)=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CN(C)c1ccc(C(=O)O)c2ccccc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(N(C)C)c5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4-(dimethylamino)naphthalene-1-carboxylic acid as starting compounds. The crude product is purified by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH3:16])=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:25]([O:28][NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH:26]=[CH2:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:25]([O:28][N:29]([C@H:13]1[CH2:12][N:11]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3])[C:15]([CH3:16])=[CH:14]1)[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])(=[O:32])=[O:31])[CH:26]=[CH2:27]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@@H]1C=C(C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a stirred suspension of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxy-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 79, 5.48 g, 15.33 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (7.92 g, 30.65 mmol) and triphenylphosphine (12.06 g, 45.98 mmol) in toluene (20 mL) was cooled in an ice-bath and added dropwise (E)-diisopropyl diazene-1,2-dicarboxylate (8.91 ml, 45.98 mmol). Reaction was let warm up to rt and continued to stir at rt for 2 h. The reaction mixture was evaporated and the crude product was loaded onto silica gel, purified via flash chromatography (750 g, 0-50%) to obtain the desired product (7.05 g, 77%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>O1CCOCC1>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][O:26][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(C)NC(COC(=O)CCC(=O)O)=C(C(=O)OCC)C1c1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixed solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.3798 g), pyridine (0.791 g) and succinic anhydride (0.1501 g) in dioxane (5 ml) was refluxed for 4.5 hours. The resultant solution was concentrated, acidified with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with dilute hydrochloric acid and water in turn. The diethyl ether extract was back-extracted with an aqueous saturated sodium bicarbonate solution and the aqueous solution was washed with diethyl ether. The aqueous solution was acidified with dilute hydrochloric acid to precipitate crystals. The crystals were collected by filtration, washed with water and then dried to give diethyl 2-methyl-4-(2-chlorophenyl)-6-(3-carboxypropionyl)oxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (419.3 mg), m.p. 130° to 131° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]O.C1COCC1.C(N(C(C)C)CC)(C)C.CS([Cl:31])(=O)=O>O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][Cl:31]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Br)c(CO)c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Br)c(CCl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2-bromo-5-nitrophenyl)methanol (6.32 g) and THF (150 mL) there were added diisopropylethylamine (5.21 mL) and methanesulfonyl chloride (2.32 mL) dropwise in that order at −10° C. under a nitrogen atmosphere. The mixture was stirred overnight at room temperature, and then ethyl acetate (400 mL) and water (200 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated oft washed with water (200 mL) and saturated aqueous sodium chloride (200 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate and the solvent in the filtrate was distilled off under reduced pressure to obtain the target compound (7.35 g) as a brown solid, which was used without purification as starting material for the following reaction (1c).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:16][C:15]([C:14]1[CH:13]=[CH:12][O:11][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:17]
Reactant: CO
Reactant: O=C(O)c1ccoc1-c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccoc1-c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 2-(3-nitrophenyl)furan-3-carboxylic acid (1.2 g) in methanol (200 mL) containing concentrated sulfuric acid (5 drops) was heated under reflux for 18 h. The reaction solution was evaporated to dryness under reduced pressure to give the title compound as a yellow solid (0.66 g). m.p.=93–94° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:4]=1.Cl.Cl.[NH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:5]1[N:4]=[C:3]([NH:29][CH2:30][CH2:31][NH:32][C:33]2[N:34]=[CH:35][C:36]([C:37]#[N:38])=[CH:39][CH:40]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.13 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo-[1,5-c]pyrimidine hydrochloride (Example 49A), 30 mg (0.15 mmol) of 6-[(2-aminoethyl)amino]pyridin-3-carbonitrile hydrochloride (Example 2A) and 0.13 ml (0.76 mmol) of N,N-diisopropylethylamine were initially charged in 1.5 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 25 mg (37% of theory) of the product as a solid.
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)CCC1=O.[CH2:18]([O:20][N:21]=[CH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])=[C:25]([CH3:36])[CH:24]=1)[CH3:19].C(N(CC)CC)C>CN(C=O)C.N1C=CC=CC=1>[CH2:18]([O:20][N:21]=[CH:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([O:30][CH2:31][CH2:32][CH2:33][C:34]2[O:9][N:8]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:35]=2)=[C:25]([CH3:36])[CH:24]=1)[CH3:19]
Reactant: C#CCCCOc1c(C)cc(C=NOCC)cc1C
Reactant: ON=Cc1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCON=Cc1cc(C)c(OCCCc2cc(-c3ccccc3)no2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of benzaldehyde oxime (45 mg, 0.372 mmol) in DMF (0.5 ml) was added dropwise to a solution of N-chlorosuccinimide (50 mg, 0.374 mmol) and pyridine (1 drop) in DMF (0.5 ml), keeping the temperature between 25-30° C. The resulting solution was allowed to stir at room temperature for 90 minutes. To this was added a solution of 3,5-dimethyl-4-(4-pentyn-1-yloxy)benzaldehyde O-ethyl oxime (49 mg, 0.189 mmol) in DMF (0.5 mL, the resulting solution was then heated at 85-90° C. for 10 minutes. To this was added, dropwise over 10 minutes, a solution of triethylamine (54 μl, 0.386 mmol) in DMF (0.5 ml), the resulting solution was then heated at 85-90° C. for 1 hour. The reaction was cooled and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (15 ml). The organic phase was washed with brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography (Ethyl acetate/Hexane 5%) gave the product (Compound 127) as a clear oil (23 mg, 32%). The structure was confirmed by the 1H nmr spectrum which is given in Table 11 below.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:4][CH:3]=1.C[N:18](C)C=O.S(Cl)(Cl)=O.[OH-].[NH4+]>O.O1CCCC1.ClCCl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([NH2:18])=[O:11])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccccc1-c1ccc(I)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1ccccc1-c1ccc(I)cc1
Temperature: 36 °C
Yield: 461.5 %

Procedure:
Add 2-(4-iodophenyl)benzoic acid (12.0 grams, 0.037 moles, preparation 55), dichloromethane (60 mL), dimethylformamide (0.5 mL, 0.0065 moles), and thionyl chloride (5.72 grams, 0.0481 moles) to a 250 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, heating mantle, condenser, and nitrogen inlet. Warm the reaction mixture to 36° C. for 45 minutes. Add thionyl chloride (1.7 grams, 0.0143 moles) and stir at 36° C. for 15 minutes. Add tetrahydrofuran (60 mL) dichloromethane (60 mL) and concentrated ammonium hydroxide (25 mL, 0.37 moles) to a 500 mL 3-neck round-bottom flask equipped with a magnetic stirrer, internal temperature probe, and cooling bath. Add the contents of the 250 mL flask to the 500 mL flask over 5 minutes while limiting the temperature to 30° C. Cool the reaction mixture to 18° C. and filter to collect the precipitate. Retain the filter cake. Transfer the filtrate to a separatory funnel and separate the phases. Concentrate the organic phase under reduced pressure (15-25 mm) to a solid, and suspend the solid in methyl-tert-butyl ether (25 mL). Isolate the solid by filtration and combine with the retained filter cake from above. Suspend the combined solids in methyl-tert-butyl ether (40 mL) at ambient temperature. Filter to isolate the solids. Suspend the solids in 50 mL water, and filter to recover the solids. Rinse the filter cake twice with water (20 mL). Dry the solids at 40° C. under reduced pressure (15-25 mm) to provide the title compound (9.7 grams, 0.030 moles, 81.1% yield). 1H NMR (acetone-d6, 500.0 MHz): δ 7.82 (d, 2H), J=8.8; 7.58 (d, 1H, J=8.2); 7.54 (td, 1H), J=7.7, 1.6; 7.46 (td, 1H, J=7.7, 1.1); 7.42 (d, 1H, J=7.6); 7.30 (d, 2H, J=8.8); 6.91 (s, 1H); 6.62 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29](O)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:27])[CH3:28])[C:21]([C:29]([N:32]2[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]2)=[O:30])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Reactant: O=S1(=O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, thiomorpholine 1,1-dioxide and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Pd].[C]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:16][CH2:17]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(C2=CCN(CC(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(CC(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 9891.4 %

Procedure:
To a solution of 4-[3-(methyloxy)-4-nitrophenyl]-1-(2-methylpropyl)-1,2,3,6-tetrahydropyridine (1.90 g, 0.0655 mmol) in MeOH was added 10% Pd/carbon (0.800 g). The resulting suspension was stirred at rt under 60 psi H2 overnight. Subsequent filtration through celite and concentration under reduced pressure afforded {2-(methyloxy)-4-[1-(2-methylpropyl)-4-piperidinyl]phenyl}amine (1.7 g, 89% yield) as a dark brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.63 (s, 1H), 6.51 (s, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 2.87 (d, J=11.36 Hz, 2H), 2.22-2.33 (m, J=11.82, 7.79, 4.03, 3.85 Hz, 1H), 2.01 (d, J=7.33 Hz, 2H), 1.88 (td, J=11.55, 2.57 Hz, 2H), 1.75 (dt, J=13.66, 6.92 Hz, 1H), 1.60-1.67 (m, 2H), 1.56 (dd, J=12.28, 3.48 Hz, 2H), 0.84 (d, J=6.60 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7](I)[CH:6]=1)[CH3:2].[CH:20]([C:23]1[N:24]=[N:25][S:26][CH:27]=1)([CH3:22])[CH3:21].C([O-])(=O)C.[K+]>CN(C=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7]([C:27]2[S:26][N:25]=[N:24][C:23]=2[CH:20]([CH3:22])[CH3:21])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Reactant: CC(C)c1csnn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(C)cn2)cc(-c2snnc2C(C)C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester (367 mg, 1 mmol), 4-isopropyl-[1,2,3] thiadiazole (640 mg, 5 mmol), palladium II tetrakis(triphenylphosphine) (35 mg, 0.03 mmol) and potassium acetate (196 mg, 2 mmol) in 10 mL of DMF was warmed to 120° C. and stirred for 16 hours. The reaction mixture was cooled and transferred directly onto a silica column and purified by liquid chromatography (0% to 10% EtOAc/hexanes) to give 250 mg of 3-(4-isopropyl-[1,2,3] thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester, MS (M+H)=368.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([N:20]1[C:25](=O)[CH:24]2[CH:22]([CH2:23]2)[C:21]1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CCOCC>[CH2:13]([N:20]1[CH2:21][CH:22]2[CH:24]([CH2:23]2)[CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C2CC2C(=O)N1Cc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: c1ccc(CN2CC3CC3C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Red-Al (70% in toluene) (24 g, 83.2 mmol) was dissolved in absolute ether (100 mL) and cooled to 0° C. under N2, then 3-benzyl-3-aza-bicyclo[3.1.0]hexane-2,4-dione (3.72 g, 18.5 mmol) was added. The mixture was stirred at 0° C. for 30 mins then stirred under reflux for 4 h. Water (50 mL) was added to the cooled solution and the mixture filtered through celite. The organic phase was dried over Na2SO4, concentrated in vacuo to give 3-benzyl-3-aza-bicyclo[3.1.0]hexane (3.0 g, 94%) as a light red oil. LC-MS: [M+H]+, 174.2, tR=0.546 min.
Reaction SMILES: C([Li])CCC.[O:6]1CCC[CH2:7]1.Br[C:12]1[C:13]([O:22][CH3:23])=[N:14][CH:15]=[N:16][C:17]=1[C:18]([F:21])([F:20])[F:19].C(OCC)=O>O>[CH3:23][O:22][C:13]1[C:12]([CH:7]=[O:6])=[C:17]([C:18]([F:21])([F:20])[F:19])[N:16]=[CH:15][N:14]=1
Reactant: COc1ncnc(C(F)(F)F)c1Br
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC=O
Solvent: O
Product: COc1ncnc(C(F)(F)F)c1C=O
Reaction time: 3 h
Yield: 15.8 %

Procedure:
30.0 ml (48.0 mmol) of n-butyllithium (1.6 mol/l n-hexane solution) was slowly added to 100 ml of tetrahydrofuran solution containing 10.3 g (40.0 mmol) of 5-bromo-4-methoxy-6-trifluoromethylpyrimidine at −65 to −60° C., and the resultant mixture was stirred at 30 minutes. Further, 3.6 g (48.0 mmol) of ethyl formate was added thereto at the same temperature, and the mixture was stirred for 3 hours at the same temperature. The resultant reaction solution was poured into water and was extracted with ethyl acetate. The organic phase thus obtained was washed with water and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resultant solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 1.3 g (yield: 15.8%) of 4-methoxy-6-trifluoromethylpyrimidine-5-carboaldehyde.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:9]>>[CH:7]1[C:6]2[CH2:5][CH2:4][CH2:3][C:2]=2[CH:1]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:9]=1
Reactant: CCOC(=O)C#N
Reactant: C#CCCCC#C
Product: CCOC(=O)c1cc2c(cn1)CCC2
Yield: 20.6 %

Procedure:
A solution of 1,6-heptadiyne (1.242 ml, 10.85 mmol) and ethyl cyanoformate (1.063 ml, 10.85 mmol) in dry degassed 1,4-dioxane (100 ml) under argon at rt was treated with cyclopentadienyl-Cobalt(I)-dicarbonyl (0.293 g, 1.628 mmol) and then heated at reflux for 18 h. Reaction was then evaporated, treated with toluene (100 ml), re-evaporated, dissolved in DCM (100 ml), filtered through a short pad of Kieselguhr, eluting with DCM, organic extracts evaporated, chromatographed (0-100% DCM:40-60 Petroleum ether then 0-10% methanol/DCM) to give product as an impure brown oil (427 mg, 21%).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Si]([C:11]([F:14])([F:13])[F:12])(C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>[F:12][C:11]([F:14])([F:13])[C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Product: OC1(C(F)(F)F)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Cyclopentanone (0.89 mL, 10 mmol) was added to a solution of TMSCF3 (0.5M in THF, 25 mL, 12 mmol) at 0° C. TBAF (1 M in THF, 0.076 mL, 0.076 mmol) was added and the resulting yellow solution was allowed to warm to rt over 2 h. 1M HCl (30 mL) was added and the resulting solution stirred 1 h at rt. Extraction with Et2O was followed by washing of the combined organics with brine and drying over anhydrous Na2SO4. Following concentration in vacuo, 1-trifluoromethylcyclopentanol (1.4 g, 88%) was isolated as a colorless liquid that was immediately converted to carbonic acid 4-nitrophenyl ester 1-trifluoromethylcyclopentyl ester analogously to carbonic acid cyclobutyl ester 4-nitrophenyl ester as described in Example 184 by substituting 1-trifluoromethylcyclopentanol (1.3 g, 8.4 mmol) for cyclobutanol with appropriate adjustments for scale and performing the reaction in a sealed tube for 40 h. The reaction volume was doubled with DCM and washed with 1M HCl (2×20 mL) followed by washing with 20 ml each of sat. NaHCO3, water, brine and finally dried over anhydrous MgSO4. Following concentration in vacuo, the residue was purified by column chromatography on SiO2 (12-25% EtOAc/hex) to produce 0.59 g (22% yield) of the desired product. 1H NMR (CDCl3, 400 MHz) δ 8.29 (m, 2H); 7.40 (m, 2H); 2.38 (m, 2H); 2.26 (m, 2H); 2.04 (m, 2H); 1.78 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][Si](C(C)(C)C)(C)C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>C1COCC1>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To an ice cooled solution of 198 mg (0.55 mmol) [4-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester in 2 ml of THF was added a 1 M solution of tetrabutylammonium fluoride hydrate in tetrahydrofuran (0.55 ml, 0.55 mmol). The reaction mixture was stirred for 1 h at ambient temperature. Diethyl ether was added and the ether solution was washed with saturated aqueous NH4Cl solution, water and brine. Evaporation of the solvent under reduced pressure gave 49 mg (0.2 mmol, 36%) of (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester as white crystals.