Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[OH:2][CH:3]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[CH2:9])[C:4]([O:6][CH3:7])=[O:5].C(O)(=O)C>CO>[CH3:9][CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[C:3](=[O:2])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(c1ccc(-c2ccccc2)cc1)C(O)C(=O)OC
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(=O)C(C)c1ccc(-c2ccccc2)cc1
Yield: 61.3 %

Procedure:
To a solution of 0.3 g of metallic sodium in 30 ml of anhydrous methanol was added a solution of 3.1 g of methyl 2-hydroxy-3-(4-biphenylyl)-3-butenoate in 10 ml of anhydrous methanol. The resulting mixture was refluxed for 30 minutes and then cooled, and thereto was added 3 ml of glacial acetic acid. The mixture was distilled at a low temperature and under reduced pressure to remove the methanol therefrom. To the residue were added ethyl acetate and water, thereby effecting ethyl acetate extraction. The ethyl acetate layer was successively washed with water, aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to obtain crude crystals. 3.0 Grams of the crude crystals was recrystallized from isopropyl alcohol to obtain 1.9 g of methyl 3-methyl-3-(4-biphenylyl)-pyruvate, m.p. 84.5°-86.5° C. The yield was 61% (theoretical value).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:3]=2)=[CH:12]1
Reactant: C1CNCCN1
Reactant: Clc1cncc(OCCc2c[nH]c3ccccc23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: c1ccc2c(CCOc3cncc(N4CCNCC4)n3)c[nH]c2c1
Temperature: 110 °C
Yield: 23 %

Procedure:
A mixture of the product from Step 1 above (1.07 g, 3.90 mmol), piperazine (0.98 g, 11.3 mmol) and K2CO3 (0.54 g, 3.9 mmol) in acetonitrile (11 mL) was heated at 85° C. for 5 h and at 110° C. for 8 h in a sealed pyrex flask. The reaction mixture was diluted with CHCl3, filtered, and concentrated in vacuo. The semi-solid residue was purified by chromatography on silica gel (11×4 cm) using CHCl3/MeOH (9: 1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short plug of alumina, covered by K2CO3, using CHCl3 as eluent. Solvent removal in vacuo furnished 0.50 g (23%) of the title compound as an oil that solidified upon standing: mp 133-135° C. HRMS m/z calcd for C18H21N5O (M)+ 323.1746, found 323.1763. Anal. (C18H21N5O) C, H, N.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([OH:29])[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.Cl[CH2:31][C:32]1[N:33]=[C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[S:35][CH:36]=1.O>CN(C)C=O>[C:37]1([C:34]2[S:35][CH:36]=[C:32]([CH2:31][O:3][C:4]3[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:31][C:32]4[N:33]=[C:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[S:35][CH:36]=4)[CH:28]=3)[CH2:7][N:8]3[CH:12]=[C:11]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]3)[N:33]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(O)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCc3csc(-c4ccccc4)n3)cc(OCc3csc(-c4ccccc4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
Sodium hydride (601, oily, 0.30 g) was added to a solution of ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1.83 g) in N,N-dimethylformamide (20 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenylthiazole (1.05 g) was added to the mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (513 mg, yield: 14%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[S:9][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:6]=1)[CH3:4].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:2][C@@H:3]([C:5]2[S:9][C:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:7][CH:6]=2)[CH3:4])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the vial containing (R)-tert-butyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.0320 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.178 mL, 1.28 mmol). The mixture was stirred at rt for 16 h and then evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give crude (R)-tert-butyl 5-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)thiophene-2-carboxylate as a brown solid. LC-MS: (FA) ES− 434.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:5].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:5]
Reactant: COCC(=O)NCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC(=O)NCC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 g tert-butyl 4-[(2-methoxyacetylamino)-methyl]-4-phenylpiperidine-1-carboxylate are placed in 4 ml dichloromethane. Then 1.7 ml trifluoroacetic acid are added and the mixture is stirred overnight at ambient temperature. The reaction mixture is made basic with potassium carbonate and the organic phase is evaporated to dryness. 610 mg (V-12) are obtained as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[H][H]>CCOC(C)=O.C(O)C.[Pd]>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2c1C=CN(C(=O)C(F)(F)F)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 91.1 %

Procedure:
Dissolve 9-fluoro-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3-dihydro-1H-benzo[d]azepine (9.4 g, 32.4 mmol) with 10% Pd/C (dry basis, Degussa type, 1.4 g, 0.65 mmol) in EtOAc/ethanol (1:1, 200 mL) and stir at ambient temperature under a balloon of hydrogen for 4.5 h. Filter the mixture through a pad of silica gel and evaporate the filtrate to obtain the desired intermediate (8.6 g, 91%). MS (ES+) m/z: 292 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[C:34]([O:36][CH2:37][CH3:38])[CH:33]=[CH:32][C:31]=4[O:39][CH2:40][CH3:41])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:42]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:42])=[O:26])=[C:21]([O:28][CH2:29][C:30]4[CH:35]=[C:34]([O:36][CH2:37][CH3:38])[CH:33]=[CH:32][C:31]=4[O:39][CH2:40][CH3:41])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(=O)OC)c1
Reactant: N
Solvent: CO
Product: CCOc1ccc(OCC)c(COc2cc(-n3cnc4cnc(CO[Si](C)(C)C(C)(C)C)cc43)sc2C(N)=O)c1

Procedure:
In a similar manner as described for example A9, 1.50 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(2,5-diethoxybenzyl)oxy]thiophene-2-carboxylate and 250 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl[CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[N:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])=[CH:20][CH:21]=1
Reactant: ClCc1ccncc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Agent: Cl
Product: Cc1cc(C#Cc2cn(Cc3ccncc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=333.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-(chloromethyl)pyridine hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].Cl>CC(OC)(C)C>[C:20]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH:9]=[C:10]([CH3:11])[CH3:12])(=[O:22])[CH3:21]
Reactant: CC(C)=CC(C)CCCCCO
Reactant: CC(=O)Cl
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCCC(C)C=C(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 76 %

Procedure:
13 g (76 mmol) of 6,8-dimethylnon-7-enol (2), 10.8 g (107 mmol) of triethylamine and 200 ml of t-butyl methyl ether (MTBE) are placed in a 500 ml round-bottomed flask equipped with a thermometer and with a dropping funnel. Cooling is carried out to 5° C. and 8.4 g (107 mmol) of acetylchloride diluted in 20 ml of MTBE are added without exceeding a bulk temperature of 10° C. The mixture is stirred at ambient temperature for 14 hours. Cooling is carried out at 5° C. and neutralization is carried out with 100 ml of a 10% hydrochloric acid solution. The phases are separated and the organic phase is washed once with 100 ml of saturated aqueous NaHCO3 solution and then with aqueous saline solution to neutrality. The organic phase is dried and filtered, and the solvent is evaporated under reduced pressure. The acetate is purified by a distillation under reduced pressure (B.p.: 58° C./0.4 torr). The yield is 76%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:36][C:33]1[CH:32]=[CH:31][C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([O:9][CH2:8][C@@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:21])[CH2:29][CH2:28]2)=[CH:35][CH:34]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Reactant: CN1CCO[C@@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@@H](COC(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
(R)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(4-Fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 6; 314 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and then reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water). The pure product was taken up in DCM (5 mL), filtered, and dried in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-(4-fluorophenyl)piperazine-1-carboxylate (100 mg, 28%) as a colourless gum.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)=[CH:9][C:8]=2[Cl:19])=[N:5][N:6]=1.[CH3:20][N:21]1[CH2:28][C@@H:27]2[C@@H:23]([CH2:24][NH:25][CH2:26]2)[CH2:22]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:19][C:8]1[CH:9]=[C:10]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[CH:11]=[CH:12][C:7]=1[C:4]1[S:3][C:2]([N:25]2[CH2:26][C@@H:27]3[C@@H:23]([CH2:22][N:21]([CH3:20])[CH2:28]3)[CH2:24]2)=[N:6][N:5]=1
Reactant: Cn1cc(-c2ccc(-c3nnc(Br)s3)c(Cl)c2)cn1
Reactant: CN1C[C@H]2CNC[C@H]2C1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1C[C@@H]2CN(c3nnc(-c4ccc(-c5cnn(C)c5)cc4Cl)s3)C[C@@H]2C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 12.7 %

Procedure:
A stirred suspension of 2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and the resulting solution was stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL) and washed with saturated NaHCO3(aq) (20 mL). The organic phase was separated and the aqueous phase was re-extracted with DCM (20 mL). The combined organic phases were concentrated in vacuo to afford the crude product as a dark brown oily residue. The crude material was purified by mass directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound as a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z 401.4 [M+H]+ [Method D]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (s, 1H), 7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s, 3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H), 2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H), 3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s., 2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH3:19][NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([N:20]([CH3:19])[CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: CNCC(O)CO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(C)CC(O)CO)c1I
Yield: 97 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with N-methyl-2,3-dihydroxypropylamine according to the conditions in Example 24g. The product was isolated in 97% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH2:11][CH2:12][OH:13])[N:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH2:11][CH2:12][O:13][CH3:16])[N:9]=[CH:10][C:3]=12
Reactant: CI
Reactant: OCCn1ncc2c(Br)cncc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCn1ncc2c(Br)cncc21
Reaction time: 2 h

Procedure:
A solution of 675 mg of 2-(4-bromo-pyrazolo[3,4-c]pyridin-1-yl)-ethanol (Intermediate 2.2; 2.79 mmol, 1 eq.) in 33 mL THF was treated at rt with 183 mg sodium hydride (55-60% suspension; 4.18 mmol, 1.5 eq.) and stirred for 30 min upon which 0.194 mL methyl iodide (3.07 mmol, 1.1 eq.) were added and stirring was continued for 2 h. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers were dried and concentrated in vacuo. Flash column chromatography provided 500 mg of the corresponding methyl ether target compound (1.95 mmol, 70% yield).
Reaction SMILES: C[O-].[Na+].[N:4](OCCC(C)C)=[O:5].[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:24])[CH2:21][CH2:22][CH3:23])=[CH:16][CH:15]=1>CO.O1CCCC1>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:24])[C:21](=[N:4][OH:5])[CH2:22][CH3:23])=[CH:16][CH:15]=1
Reactant: CCCC(=O)c1ccc(SC)cc1
Reactant: CC(C)CCON=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=NO)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
11.0 g (0.206 mol) of sodium methoxide is suspended in 130 ml of methanol. Then isoamyl nitrite (27 ml, 0.206 mol) and 25 g (0.129 mol) of 1-(4-Methylsulfanyl-phenyl)-butan-1-one dissolved in 70 ml of tetrahydrofuran (THF) are added and the reaction solution is stirred at room temperature for 1.5 days. After concentrating, water and acetic acid are added to neutralise. The crude product is extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (15:85) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ[ppm]: 1.14 (t, 3H), 2.52 (s, 3H), 2.72 (q, 2H), 7.25 (d, 2H), 7.89 (d, 2H), 8.01 (s, 1H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9](B(O)O)=[C:8]([F:16])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].Br[C:18]1[CH:19]=[N:20][C:21]([Cl:24])=[N:22][CH:23]=1.C1COCC1.O.O.O.O.O.O.O.O.O.O.B(O)([O-])[O-].B(O)(O)O.B(O)(O)O.B(O)(O)O.[Na+].[Na+]>O>[CH2:1]([C:6]1[CH:11]=[C:10]([F:12])[C:9]([C:18]2[CH:19]=[N:20][C:21]([Cl:24])=[N:22][CH:23]=2)=[C:8]([F:16])[CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Clc1ncc(Br)cn1
Reactant: CCCCCc1cc(F)c(B(O)O)c(F)c1
Agent: OB(O)O
Agent: [Na+]
Agent: [O-]B([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1cc(F)c(-c2cnc(Cl)nc2)c(F)c1

Procedure:
A mixture of 0.22 mol of 4-pentyl-2,6-difluorophenylboronic acid (prepared from 5-pentyl-1,3-difluorobenzene and trimethyl borate using n-butyllithium), 0.18 mol of 5-bromo-2-chloropyrimidine, 550 ml of THF, 75 ml of an aqueous buffer solution (pH=8), 230 ml of an aqueous disodium tetraborate decahydrate solution (4%), 200 ml of water and 2 g of tetrakis[triphenylphosphine]palladium (0) is heated at the boil for 20 hours. Customary work-up gives the product, which can be further processed without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[N:30]1([NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NN3CCOCC3)ccc21
Yield: 82.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid morpholin-4-ylamide (100 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 4-aminomorpholine (28 mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 493.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 9.49 (s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.78-7.59 (m, 2H), 7.47 (d, 1H), 7.34 (d, 1H), 3.78-3.56 (m, 7H), 2.93-2.84 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[CH:6]2.[Li]C.I[CH2:15][CH2:16][CH3:17].[NH4+].[Cl-]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH2:15][CH2:16][CH3:17])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)C=CC2
Reactant: CCCI
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC1C=Cc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 108.3 %

Procedure:
A solution of 5-methoxy-1H-indene (0.895 g, 6.12 mmol) in anhydrous Et2O (7.5 mL) was treated with 1.4M MeLi in Et2O (4.7 mL, 6.58 mmol) added dropwise over 10 minutes. The resulting hazy solution was stirred at room temperature an additional 15 minutes, then cooled in an ice bath and treated with iodopropane (1.00 mL, 10.3 mmol). The mixture was stirred at ice bath temperature with gradual warming to room temperature. After stirring at room temperature overnight, the mixture was treated with saturated aq. NH4Cl (10 mL) and Et2O (15 mL) and shaken. The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to afford a mixture (1.248 g) of 5-methoxy-1-propyl-1H-indene and 6-methoxy-1-propyl-1H-indene as an oil.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]=[O:26])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1.[CH2:29]([Mg]Br)[CH3:30].OP([O-])(O)=O.[K+]>O1CCCC1.COC(C)(C)C>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([CH:25]([OH:26])[CH2:29][CH3:30])=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([C:21]([F:22])([F:24])[F:23])[CH2:17][CH2:16]3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Reactant: CC[Mg]Br
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCC(O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 530 mg of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carbaldehyde in 43 ml tetrahydrofuran at 0° C. was slowly added 2.2 ml of a molar solution of ethylmagnesium bromide in tert-butyl methyl ether. The reaction mixture was stirred at 0° C. for one hour then poured onto an aqueous solution of KH2PO4 and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 545 mg 1-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-propan-1-ol which was used without further purification.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(C(C)C)CC)(C)C.[I-].[Na+].Br[CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=1>C(O)(C)C>[I:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:30][CH:31]=1
Reactant: BrCCOc1ccc(I)cc1
Reactant: CCCCCCCCCCCCN
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCNCCOc1ccc(I)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of dodecylamine (30 g, 162 mmol), diisopropylethylamine (22 ml, 128 mmol), sodium iodide (1.3 g, 8.5 mmol), 1-[2-bromoethoxy]-4-iodobenzene (13.9 g, 42.5 mmol) and isopropanol (250 ml) was stirred and refluxed for 24 h. After cooling to r.t., the mixture was filtered, washed with dichloromethane and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 50:1 to 20:1) to afford the title compound (15 g, 82%) as a white solid.