Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13].[BrH:20]>C(O)(=O)C>[BrH:20].[Br:20][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13]
Reactant: O=c1[nH]cnc2ccc(C(O)c3ccccc3)cc12
Agent: Br
Solvent: CC(=O)O
Product: O=c1[nH]cnc2ccc(C(Br)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of 4 parts of intermediate 38, namely 6-(hydroxyphenylmethyl)-4(3H)-quinazolinone, and 67.7 parts of a solution of hydrobromic acid in acetic acid 30% was stirred for 24 hours at room temperature. The reaction mixture was evaporated and the residue was co-evaporated with methylbenzene, yielding 6.5 parts (100%) of 6-(bromophenylmethyl)-4(3H)-quinazolinone monohydrobromide (interm. 48).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.Br[C:17]1[CH:33]=[CH:32][C:20]2[CH2:21][CH2:22][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:25][C:19]=2[C:18]=1[O:34][CH3:35]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:34][C:18]1[C:19]2[CH2:25][CH2:24][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:22][CH2:21][C:20]=2[CH:32]=[CH:33][C:17]=1[CH3:1]
Reactant: O=C([O-])[O-]
Reactant: COc1c(Br)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 115 °C
Yield: 82.5 %

Procedure:
Add potassium carbonate (5.65 g, 40.91 mmol), tetrakis(triphenylphosphine)palladium (1.576 g, 1.363 mmol) and trimethylboroxine (2.053 g, 2.3 mL, 16.35 mmol) to a solution of 7-bromo-6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.8 g, 13.63 mmol) in dimethylformamide (40 mL) under nitrogen. Heat the mixture to 115° C. for 6 h. Add water and extract the aqueous phase twice with EtOAc. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 19:1) to obtain the desired intermediate as a solid (3.23 g, 83%). GC-MS m/z 287 (M+).
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CN(C)C=O>[CH2:1]([C:8]1([N:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][CH:11]([O:14][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(O)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(Cc2ccccc2)CCC(OCc2ccc(F)cc2)CC1
Temperature: 0 °C
Yield: 54 %

Procedure:
2.00 g of 4-benzyl-4-dimethylaminocyclohexanol were dissolved in 20 ml of dimethylformamide; 1.06 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 1.36 g of 4-fluorobenzyl chloride were added dropwise in the course of 30 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (2.78 g) was separated on silica gel with hexane/ethyl acetate (V:V=1:1). 1.58 g of [1-benzyl-4-(4-fluorobenzyloxy)cyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 890 mg of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone (white solid).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.NCC(OCC1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+].N1C=CC=CC=1.Cl[C:38]([O:40][CH:41]([Cl:43])[CH3:42])=[O:39]>C(Cl)Cl.O>[Cl:43][CH:41]([O:40][C:38]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:39])[CH3:42]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(Cl)OC(=O)NCC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Benzyl 2-aminoacetate was generated from a treatment of benzyl 2-aminoacetate hydrochloride (Aldrich) in methylene chloride with aqueous sodium bicarbonate solution followed by water wash. To a cooled solution of benzyl 2-aminoacetate (1.837 g, 11.1 mmol) and pyridine (1.1 g, 1.1 mL, 13.9 mmol) in methylene chloride (17 mL) at −78° C., was added slowly 1-chloroethyl chloroformate (Aldrich, 1.67 g, 11.7 mmol) over ˜10 min. The reaction mixture was allowed to stir at −78° C. for 3 h, giving a white precipitate. This cold reaction mixture was filtered to remove the solid and the filtrate was concentrated to dryness, giving the crude benzyl 2-((1-chloroethoxy)carbonylamino)acetate which was used for the next step without further purification.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[C:7]([NH:9][C:10]1[CH:24]=[CH:23][C:13]([O:14][CH2:15][CH2:16][NH+:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:12]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH:11]=1)=[O:8].[OH-].[Na+]>O>[OH2:3].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[C:7]([NH:9][C:10]1[CH:24]=[CH:23][C:13]([O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[C:12]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH:11]=1)=[O:8]
Reactant: COc1cccc(C(=O)Nc2ccc(OCC[NH+]3CCOCC3)c(-c3ccnn3C)c2)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c(-c3ccnn3C)c2)c1

Procedure:
100 mg of 4-(2-(4-(3-methoxybenzamido)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl)morpholin-4-ium chloride were added to 3 mL of H2O in a 4 mL vial. The solution was stirred until it became clear. 225 μL of 1 N NaOH was added to the vial to reach a pH of ˜8. A white precipitate formed. The solution was stirred for 1 hour at room temperature. The crystalline materials formed on the side of the vial were scraped off, and the solution was filtered using centrifuge tube filters. The material was dried overnight in the hood.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
A suspension of 2-bromo-7-hydroxymethylimidazo [5,1-b]thiazole (24 mg, 0.10 mmol) in dichloromethane (3.5 ml) was added to a solution of pyridinium dichromate (47 mg, 0.13 mmol) in dichloromethane (1.5 ml), and the mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, 4A molecular sieves were added thereto, and the mixture was stirred at room temperature for 20 min. The procedure consisting of filtering the reaction mixture through Celite, adding ethyl acetate to the residue, stirring the mixture, and filtering the stirred mixture through Celite was repeated a few times. The filtrates were combined, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (11 mg, 47%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][NH:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][N:25]3[CH3:31])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:8][CH:9]=1
Reactant: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)NCCC2(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCCC(C=Cc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[3-(4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester (0.36 g, 0.88 mmole) in 10 mL of THF was cooled to −78° C. and was treated with 1.1 mL of a 1M lithium bis(trimethylsilyl)amide solution in hexanes. After 30 minutes at −78° C., 0.06 mL of methyl iodide was added. The mixture was stirred at room temperature for 7 hours, quenched by the addition of 10 mL of saturated aqueous ammonium chloride solution and extracted with two 10 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 5% ethyl acetate in hexanes) to yield 0.23 g of 4-[3-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-oct-1-enyl]-benzoic acid methyl ester as a pale yellow oil.
Reaction SMILES: O1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]=[O:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1.O1CCCC[CH:27]1OC1C=C(C23CCC(CCO)(CC2)CO3)C=CC=1.O(C1C=C(C23CCC(CCO)(CC2)CO3)C=CC=1)C1C=CC=CC=1>>[O:7]([C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][CH:24]=[O:25])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:27]=1
Reactant: OCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: O=CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: OCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2
Product: O=CCCC12CCC(c3cccc(Oc4ccccc4)c3)(CC1)OC2

Procedure:
3-(1-(3-Phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (clear oil) was prepared using a procedure analogous to 3-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal except that 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol was replaced with 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol. LCMS, [M−H]+=335.2. 1H NMR (500 MHz, CDCl3) δ 9.78 (t, J=1.5 Hz, 1H), 7.34-7.23 (m, 3H), 7.14-7.03 (m, 3H), 7.01-6.95 (m, 2H), 6.87-6.81 (m, 1H), 3.81-3.78 (m, 2H), 2.43-2.36 (m, 2H), 2.09-1.94 (m, 4H), 1.69-1.58 (m, 4H), 1.54-1.47 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:29][N:30]([CH3:45])[CH2:31][CH2:32][CH2:33][N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][OH:44])[CH:35]=[O:36].C(Cl)(Cl)Cl>ClCCl>[CH3:45][N:30]([CH3:29])[CH2:31][CH2:32][CH2:33][N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][O:44][C:27](=[O:28])[NH:26][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:35]=[O:36]
Reactant: CN(C)CCCN(C=O)c1ccccc1CO
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCc1ccccc1N(C=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Triethylamine (0.65 ml) and octadecyl isocyanate (1.47 ml) were added to a solution of N-[3-(dimethylamino)propyl]-[2-(hydroxymethyl)phenyl]formamide (1.01 g) in dichloromethane (10 ml). After being stirred for 19 hours at room temperature, the reaction mixture, with chloroform added thereto, was washed with water, dried over sodium sulfate anhydride, and then concentrated. The residue was purified by silica gel column chromatography (silica gel 40 g, chloroform:methanol=50:1-10:1), thereby yielding 1.36 g of the aimed compound as white wax.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O.[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O.O1CCCC1.O.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:11](=[O:13])[CH:10]=[CH:9][CH2:8][Br:7])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=C(O)/C=C/CBr
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(C=CCBr)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
A 2.88 mL (4.19 g; 0.033 mole) portion of oxalyl chloride was added to 2.47 g (0.015 moles) of 4-bromo crotonic acid suspended in 25 mL of dichloromethane. To this was added 3 drops of N,N-dimethylformamide. After stirring for about 1 ½ hours, the solvents were removed in vacuo, and the residual oil was dissolved in 20 mL of tetrahydrofuran. This solution was cooled in an ice bath, and a solution of 4.72 g (0.015 moles) of N-(3-bromophenyl)-4,6-quinazolindiamine in 50 mL of tetrahydrofuran was added dropwise. This was followed, still with cooling by the dropwise addition of 2.61 mL (1.99g; 0.015 moles) of diisopropylethylamine in 10 mL of tetrahydrofuran. After cooling and stirring an hour, 80 mL of ethyl acetate and 100 mL of water were added. The layers were separated, and the aqueous layer was extracted with 100 mL of 1:1 tetrahydrofuran ethyl acetate. The combined organic layers were washed with 50 mL of brine, then dried over sodium sulfate. The solution was taken to a solid in vacuo. This solid was digested for an hour with 100 mL of ethyl acetate to give 5.87 g (84%) of product. Mass spectrum (m/e) M+H 460.8, 62.8, 464.8.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccccn2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2ccccn2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-[3-(2-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 58) (247 mg, 0.60 mmol) was treated with trifluoroacetic acid (7 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichloromethane to afford the title compound as an oil (262 mg).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:25][C:26]1([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][C:31]([C:26]1([NH:25][C:13]([C:12]2[C:6]3[C:7](=[N:8][CH:9]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:5]=3)[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[CH:11]=2)=[O:14])[CH2:30][CH2:29][CH2:28][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)(O)C1(N)CCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)C1(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(C4CC4)nc23)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
In a round-bottomed flask were combined 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.45 mmol), 2-(1-amino-cyclopentyl)-propan-2-ol hydrochloride (115 mg, 0.64 mmol), EDC (95 mg, 0.50 mmol), and HOBt (67 mg, 0.50 mmol). Then added DMF (2 mL) followed by i-Pr2NEt (0.20 mL, 1.12 mmol). The reaction mixture was stirred at room temperature overnight then quenched with H2O and extracted with EtOAc (3×). The combined organics were washed with H2O (3×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 12 g of SiO2 using EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 209 mg (96%) of 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-hydroxy-1-methyl-ethyl)-cyclopentyl]-amide as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of methyl 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.79 g) in a mixture of tetrahydrofuran (20 mL) and methanol (15 mL) was added 1M aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at 50° C. for 30 min. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was washed with diethyl ether three times. The diethyl ether layers were combined and extracted with water. The aqueous layers were combined and 1M hydrochloric acid (15 mL) was added to the mixture. The resulting white suspension was filtered to give the title compound (1.02 g, 69%) as a pale orange solid. MS 451 (MH+).
Reaction SMILES: N/[CH:2]=[N:3]/[C:4](/[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:5](\[C:11]#[N:12])/[C:6]([O:8][CH2:9][CH3:10])=[O:7].[ClH:23]>O>[Cl:23][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=[CH:2][N:12]=1
Reactant: Cl
Reactant: CCOC(=O)/C(C#N)=C(/N=C/N)NCc1ccc(OC)cc1
Solvent: O
Product: CCOC(=O)c1c(Cl)ncnc1NCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
(E)-Ethyl 3-((E)-(aminomethylene)amino)-2-cyano-3-((4-methoxybenzyl)amino)acrylate (1.24 g, 3.49 mmol) was dissolved in 23 mL hydrochloride acid (4M in dioxane, 90.64 mmol) and the mixture was stirred at room temperature overnight. The mixture was poured into 400 mL water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude was purified using SP1® Purification System (0% to 25%, hexane-ethyl acetate) to give 376 mg (34% yield) of the title compound as a white solid.
Reaction SMILES: COCC([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][O:16][CH3:17])[CH2:10][CH2:9]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:17][O:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]1
Reactant: COCC(=O)OCC1CCN(C(=O)COC)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCCN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A solution of (1-(2-methoxyacetyl)piperidin-4-yl)methyl 2-methoxyacetate from the previous step (6.5 g, 25.1 mmol) in THF (10 mL) was added drop-wise to a 1 M solution of LiAlH4 in THF (55.0 mL, 55.0 mmol) under argon. The reaction mixture was stirred at room temperature for 2 days and then cooled to 0° C. Water (2.0 mL) was added drop-wise. A gelatinous white solid formed. 0.2M aq NaOH solution (2.0 mL) was added drop-wise. Water (5.0 mL) was added and the resulting mixture stirred at room temperature for 3 h. The white solid was removed by filtration. The filtrate was concentrated in vacuo and dried on an Isolute HM-N cartridge (eluting with EtOAc). The resulting organic solution was dried in vacuo to give (1-(2-methoxyethyl)piperidin-4-yl)methanol (3.65 mg, 84%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[H-].[Na+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O>[CH3:17][O:18][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6]
Reactant: COCCl
Reactant: CON(C)C(=O)c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc(C(=O)N(C)OC)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
69.0 g (380 mmol) of B5 were dissolved in 500 ml of dry dimethylformamide, cooled to 0° C. and 11.5 g (480 mmol) sodium hydride were added and the mixture was allowed to stir for 10 minutes. A solution of 31.2 ml (418 mmol) (chloromethyl)methylether in 100 ml of dry diemthylformamide was added at this temperature over a period of 30 minutes. After stirring at room temperature overnight, the solvent was distilled off and the residue was partitionated between 400 ml of dichloromethane and 100 ml of water. The organic layer was washed with 50 ml of aqueous sodium hydrogen carbonate and two times with water (80 ml each) and finally dried over sodium sulfate. Removing the solvent in vacuo yielded 73.5 g (87%) B6 as a colorless oil which was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15](Br)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1.[Li]CCCC.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15]([CH:31]([OH:32])[C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Reactant: O=Cc1cccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C(O)c3cccs3)c(C3OCCO3)cc21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. tetrahydrofuran (3.0 mL) solution of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (253 mg, 0.75 mmol) was added n-BuLi (1.6 M in hexane, 0.49 mL). The reaction mixture gradually thickened over 45 min. A solution of thiophene-2-carboxaldehyde (0.09 mL, 0.94 mmol) in tetrahydrofuran (0.75 mL) was added dropwise to the above slurry. The reaction mixture rapidly became homogeneous and was stirred at −78° C. for 45 minutes. Saturated ammonium chloride and ethyl acetate were added and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give a yellow oil which was purified by preparative thin layer chromatography (15% ethyl acetate/hexane) to give 2-(1,3-dioxolan-2-yl)-3-[1-hydroxy-1-(thiophene-2-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a waxy solid (190 mg, 67%).