Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C.[OH-].[Na+].ClCCl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH2:2]1)[CH3:15]
Reactant: CCOC(=O)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CC1CNc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
Ethyl indole-3-acetate (4 g, 19 mmol, 98%) was taken up in acetic acid (40 cm3) and sodium cyanoborohydride (4 g, 63 mmol) was added. The reaction was stirred at room temperature for 2 h, then diluted with aqueous sodium hydroxide until basic. The aqueous mixture was extracted with ethyl acetate and the organic layer was separated, dried and concentrated to dryness under reduced pressure. The solid obtained was taken up in dichloromethane and chromatographed on silica eluting with dichloro-methane with increasing volumes of methanol. The product containing fractions were combined and concentrated to yield ethyl-2,3-dihydro-indole-3-acetate as a solid (3 g, 15 mmol, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36]Cl)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:36][CH2:35][O:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([OH:38])=[O:26])[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1ccccc1OCCCl
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccsc1
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2Cc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.3 g (10 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 2.6 g (12 mmol) of 2-(2-chloro-ethoxy)-benzoic acid ethyl ester. After standard work-up and recrystallisation with ethanol, 1.8 g (37% of yield) of the expected acid were obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C)C(=O)C>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:17][CH2:16]1
Reactant: N#Cc1ccc(Br)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(C#N)cc2C(F)(F)F)CC1
Temperature: 95 °C
Reaction time: 14 h

Procedure:
A mixture of 4-bromo-3-(trifluoromethyl)-benzonitrile (Yonezawa et al., Synthetic Communications (1996) 26, 1575-8; 2.47 g, 12 mmol), 1-methylpiperazine (Fluka, Buchs, Switzerland, 5.33 mL, 48 mmol) and 15 mL N,N-dimethylacetamide is stirred in a tightly closed vessel for 14 hours at 95° C. After cooling, the reaction mixture is evaporated to dryness under reduced pressure and the residue is treated with a half-saturated aqueous solution of sodium carbonate and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated off under reduced pressure. The crude product is purified by column chromatography on silica gel, eluent methylene chloride/methanol to give 4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)-benzonitrile as a pale yellow oil.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]1[C:14]([CH2:15][C:16]([OH:18])=O)=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:4])#[N:2].[OH2:22].N>>[O:18]=[C:16]1[CH2:15][C:14]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=2[O:8][C:7]2[CH:6]=[C:5]([CH:3]([CH3:4])[C:1]([NH2:2])=[O:22])[CH:21]=[CH:20][C:19]1=2
Reactant: O
Reactant: CC(C#N)c1cccc(Oc2ncccc2CC(=O)O)c1
Agent: N
Product: CC(C(N)=O)c1ccc2c(c1)Oc1ncccc1CC2=O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The mixture of 1.3 g of 2-[3'-(α-cyanoethyl)-phenoxy]-3-pyridylacetic acid and 30 g of polyphosphoric acid was stirred at 150° C. for 2 hours. After cooling, to this was added ice-water and the mixture was alkalified with 10% ammonia water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the oil, which was chromatographed over silica gel, eluted with chloroform/ethanol (50/1), and there was obtained a solid substance. This was recrystallized from methanol to give 250 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-9-yl)-propionamide as pale yellow powder having a melting point of 89°-90° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:3]1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(C(C)C)CC)(C)C>CC#N>[CH3:1][C@@H:2]1[CH2:3][N:4]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:5][CH2:6][N:7]1[CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: C[C@@H]1CN(C2CCCCc3ccccc32)CCN1
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN1CCN(C2CCCCc3ccccc32)C[C@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
To a solution of (3R)-3-methyl-1-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazine (620 mg, 2.537 mmol) in MeCN was added methyl 2-bromoacetate (466 mg, 3.044 mmol) followed by diisopropylethylamine (0.884 ml, 5.074 mmol). The reaction mixture was stirred at rt for 5 h. The solvent was evaporated under high vacuum and the residue was loaded on column (SiO2, hexane to hexane/EtOAc=100:10 to 100:20 to 100:30 to 100:40) to give methyl 2-((R)-2-methyl-4-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)piperazin-1-yl)acetate (800 mg, 99.6% yield) as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[Br:17][C:14]1[CH:13]=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(-c2cccc(OC)c2)c1
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(OC)ccc2Br)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
3,3′-dimethoxybiphenyl (5.0 g, 23.34 mmol) was dissolved in a dimethylformamide solvent and cooled to 0° C. N-bromosuccinimide (4.15 g, 23.34 mmol) was dissolved in a dimethylformamide solvent (63 ml) and added slowly to a solution of 3,3′-dimethoxybiphenyl for about 1.5 hours. The mixture was stirred at room temperature for about 12 hours and distilled water was added thereto, followed by stirring for about 10 minutes. The resultant was filtered three times with hexane and the filtrate was washed three times with distilled water and dried over sodium sulfate. Hexane was removed under reduced pressure to obtain a desired product (Yield: 6.70 g (98%)). The obtained product was identified as 2-bromo-5,3′-dimethoxybiphenyl through the nuclear magnetic resonance (NMR) spectrum, corresponding to the compound I of the reaction scheme 1.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)Cl.[F:15][C:16]1[C:17]([C:32]2[N:33]=[C:34]([S:42][CH3:43])[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=23)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:22]=[CH:21]2>>[F:15][C:16]1[C:17]([C:32]2[N:33]=[C:34]([S:42]([CH3:43])=[O:9])[N:35]3[CH:40]=[CH:39][N:38]=[C:37]([NH2:41])[C:36]=23)=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:22]=[CH:21]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12
Solvent: ClCCl
Product: CS(=O)c1nc(-c2ccc3ccc(-c4ccccc4)nc3c2F)c2c(N)nccn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (0.013 g, 0.000075 mol) in DCM (0.4 g, 0.005 mol) was added slowly to a solution of 1-(8-fluoro-2-phenyl-quinolin-7-yl)-3-methylsulfanyl-imidazo[1,5-a]pyrazin-8-ylamine (30 mg, 0.000075 mol) in DCM (2 mL, 0.04 mol) at −78° C. The reaction mixture was allowed to stir at that temp for 30 min. The reaction mixture was transferred to an ice-bath and stirred for 1 h. 50% consumption of SM was observed. The reaction mixture was stirred in ice-bath for 1 h. An additional 0.5 eq of m-chloroperbenzoic acid was added to the reaction mixture and the reaction mixture was warmed to rt and stirred for 2 h. The reaction mixture was concentrated in vacuo. Purification by prep TLC (7% MeOH in DCM) afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ=5.13 (br. s., 2H), 7.32 (d, J=5.05 Hz, 1H), 7.48-7.60 (m, 3H), 7.69 (dd, J=8.46, 6.44 Hz, 1H), 7.76-7.81 (m, 1H), 8.06 (d, J=8.84 Hz, 1H), 8.15 (d, J=5.05 Hz, 1H), 8.25 (dd, J=8.21, 1.39 Hz, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 417.95 (100)[MH+]. HPLC: tR=2.63 min (Open Lynx polar—5 min).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:3]=1.O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:3]=1
Reactant: Cc1cc(O)nc(/C=C/c2cccc(C#N)c2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nc(/C=C/c2cccc(C#N)c2)n1
Yield: 99.4 %

Procedure:
In analogy to example 12c), by heating (E)-3-[2-(4-hydroxy-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (1 g, 4.21 mmol) in POCl3 (7.7 ml, 84.3 mmol) at 130° C. for 4.5 h there was obtained (E)-3-[2-(4-chloro-6-methyl-pyrimidin-2-yl)-vinyl]-benzonitrile (1.07 g, 99%) as an orange solid. EI mass spectrum, m/e: 255 (M calculated for C14H10ClN3: 255).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][C:9]1[CH:10]=[C:11]([OH:23])[CH:12]=[C:13]([CH3:22])[C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[O:27]>O>[CH3:24][N:25]([CH3:29])[C:26](=[O:27])[O:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[C:9]([CH3:8])[CH:10]=1
Reactant: Cc1cc(O)cc(C)c1Sc1ccccn1
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)N(C)C)cc(C)c1Sc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 240 mg. of sodium hydride in 20 ml. of dry tetrahydrofuran is added a solution of 2.31 g. of 3,5-dimethyl-4-(2-pyridylthio)phenol in 30 ml. of dry tetrahydrofuran. After the effervescence has subsided, a solution of 1.1 g. of N,N-dimethylcarbamoyl chloride in 10 ml. of dry tetrahydrofuran is added dropwise. The reaction mixture is stirred at ambient temperature for 16 hours, and then under reflux for 4 hours. The reaction mixture is cooled to room temperature, and then diluted with an excess of water. The product is extracted into ethyl acetate. The ethyl acetate is washed with water, dried using anhydrous magnesium sulfate, and then evaporated in vacuo to give crude 3,5-dimethyl-4-(2-pyridylthio)phenyl N,N-dimethylcarbamate. The crude product can be purified further by recrystallization.
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[CH2:16][C@@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5](Cl)[N:4]=1>CO>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[CH2:16][C@@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5]([NH2:1])[N:4]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Reactant: N
Solvent: CO
Product: Nc1nc(N)c2ncn([C@@H]3C=C[C@H](CO)C3)c2n1
Temperature: 75 °C
Yield: 80 %

Procedure:
Liquid ammonia is passed into a solution of cis-(±)-2-amino-6-chloro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purine (0.265 g, 1 mmol) in methanol (10 mL) at -80° C. in a bomb. The bomb is sealed and heated at 75° C. for 48 hours. The bomb is cooled to room temperature and the ammonia and methanol are evaporated. The residue is purified by silica gel chromatography using 15:1 chloroform methanol as eluent to give cis-(±)-2,6-diamino-9-[4-(hydroxymethyl)-2-cyclo-penten-1-yl]-9H-purine (0.196 g, 80%). M.pt. 152°-155° C. MS (30 ev, 200° C.): m/e 246 (M+), 229 (M+-17), 216 (M+-30).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[N:29]=[C:28]([O:30][CH2:31][C:32]([O:34]CC3C=CC=CC=3)=[O:33])[CH:27]=[CH:26][CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:42])[N:10]1[CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[NH:49][S:50]([CH3:53])(=[O:52])=[O:51].CN(C=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][CH2:22][CH2:23][C:24]2[N:29]=[C:28]([O:30][CH2:31][C:32]([OH:34])=[O:33])[CH:27]=[CH:26][CH:25]=2)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:42])[N:10]1[CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH:44]1[NH:49][S:50]([CH3:53])(=[O:51])=[O:52]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OCC(=O)OCc3ccccc3)n2)C1c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NCCc2cccc(OCC(=O)O)n2)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
To a mixed liquid of 420 mg of benzyl ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetate, 5 ml of DMF, and 5 ml of ethanol was added 84 mg of 5% palladium/carbon, followed by stirring at room temperature for 15 minutes under a hydrogen atmosphere. After separating the palladium/carbon by filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 78 mg of ({6-[2-({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]pyridin-2-yl}oxy)acetic acid as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]3[CH:29]=[C:30]([CH:34]=O)[CH:31]=[N:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>ClCCCl>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]3[CH:29]=[C:30]([CH2:34][NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:31]=[N:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: CN(C)CCN
Reactant: O=Cc1cncc(-c2ccc3[nH]ccc3c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)CCNCc1cncc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
Sodium triacetoxyborohydride (855 mg, 4.05 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(1H-indol-5-yl)-pyridine-3-carbaldehyde (300 mg, 1.35 mmol) and N,N-dimethylethylene diamine (237 mg, 2.7 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 48 h, and then the volatiles were removed in the presence of celite. The product was eluted from the celite through silica gel (elution with methanol/dichloromethane) to give 328 mg of product. LC/MS: Retention time, 0.43 min; (M+H)=295.19.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12](C(=O)C)=[C:11]([F:18])[C:10]=1[CH3:19])([CH3:7])[CH3:6])[CH3:2].ClC1C=CC=[C:24]([C:28]([O:30]O)=[O:29])C=1>>[CH2:1]([O:3][C:4](=[O:20])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:30][C:28](=[O:29])[CH3:24])=[C:11]([F:18])[C:10]=1[CH3:19])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)c(F)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(C)=O)c(F)c1C

Procedure:
In analogy to the procedure described in example 32D], 2-(4-acetyl-3-fluoro-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester was oxidized with a total of 4.5 equivalent of 3-chloro perbenzoic acid during 6 day to give the title compound as orange semisolid residue.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([C:17]12[O:24][CH2:23][C:20]([CH3:25])([CH2:21][O:22]1)[CH2:19][O:18]2)[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])C1C=CC=CC=1>C(OCC)(=O)C>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][C@H:11]([NH2:10])[C:17]12[O:18][CH2:19][C:20]([CH3:25])([CH2:21][O:22]1)[CH2:23][O:24]2
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2
Solvent: CCOC(C)=O
Product: CC(C)(C)C[C@H](N)C12OCC(C)(CO1)CO2
Reaction time: 4 h
Yield: 84.5 %

Procedure:
[3,3-Dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]carbamic acid benzyl ester (15 g) was dissolved in ethyl acetate (300 ml) and after degassing with nitrogen, 10% Pd—C (1.5 g) was added under nitrogen atmosphere. The reaction mixture was hydrogenated at 50 psi for 4 h. The solution was filtered through celite and washed with EtOAc. The solvent was removed to give 3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butylamine (8 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)([CH3:6])[C:3]([NH2:5])=O.Cl>C1COCC1>[CH3:6][C:2]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][CH:10]=2)([CH3:1])[CH2:3][NH2:5]
Reactant: CC(C)(C(N)=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CN)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
2-Methyl-2-(5-nitro-1H-indol-2-yl)propanamide (200 mg, 0.81 mmol) was suspended in THF (5 ml) and cooled to 0° C. Borane-THF complex solution (1.0 M, 2.4 mL, 2.4 mmol) was added slowly and the mixture was allowed to stir overnight at room temperature. The mixture was cooled to 0° C. and carefully acidified with 3 N HCl. THF was evaporated off, water was added and the mixture was washed with ethylacetate. The aqueous layer was made alkaline with 50% NaOH and the mixture was extracted with ethylacetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 2-methyl-2-(5-nitro-1H-indol-2-yl)propan-1-amine (82 mg, 43%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:10]=1[CH:16]=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 3-(2-formyl-4-hydroxy-phenyl)-acrylic acid tert-butyl ester (4.97 g, 20.0 mmol) in DMF (40 mL) was added benzyl bromide (2.85 mL, 24.0 mmol) and Cs2CO3 (7.82 g, 24.0 mmol). The suspension was stirred at 80° C. for 30 min, and TLC indicated the reaction was complete. The mixture was quenched with H2O (500 mL) and extracted with EtOAc (2×100 mL). The combined organics were dried (Na2SO4) and concentrated to a residue, which was purified by silica gel chromatography (hexanes/EtOAc 9/1) to afford the title compound as yellow solid (6.70 g, 99%).
Reaction SMILES: [Br:1]Br.[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[CH:7]=1)[CH3:4]>C(O)(=O)C>[CH2:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([Br:1])=[C:8]([CH3:12])[CH:7]=1)[CH3:4]
Reactant: BrBr
Reactant: CCSc1cccc(C)c1
Solvent: CC(=O)O
Product: CCSc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (2.2 ml) was added to a solution of 1-(ethylthio)-3-methylbenzene (6.6 g) in acetic acid (20 ml) at 0° C. The mixture was stirred at RT for 2 h then the solvent removed under reduced pressure. The residue was purified by chromatography on silica eluting with DCM. Yield 6.6 g
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.O[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:1]1([O:6][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1CC=CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CC=CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 3-cyclopenten-1-ol (15.3 g), N-hydroxyphthalimide (29.7 g) and triphenylphosphine (47.7 g) in tetrahydrofuran (250 ml) was added diethyl azodicarboxylate (31.7 g) at 40° to 50° C. After stirring at 45° C. for 2 hours, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The separated organic layer was washed with 5% aqueous solution of sodium bicarbonate, brine, successively and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residual oil was subjected to column chromatography on silica gel. The desired product was eluted with 15% ethyl acetate in n-hexane to give N-(3-cyclopenten-1-yloxy)phthalimide (25.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]=[O:15]>C(O)(C)(C)C.CS(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C=O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1CCO
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 64.1 %

Procedure:
A solution of potassium tertiary-butylate (1.8 g, 8 mmol) in tert.-butanol (20 ml, synthesis quality, 99%) was added to 2,6-dinitrotoluene (18.2 g, 0.1 mol, dried for 3 d in high vacuum over silica gel) and paraformaldehyde (3 g, 0.1 mol) in DMSO (50 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å). After the addition of the potassium tertiary-butylate solution, a color change from yellow to deep violet occurred. The solution was stirred for 5 min at room temperature and for 10 min at 70° C. (oil bath temperature). It was then left to cool to room temperature, and the mixture was neutralized with conc. HCl, and diluted with H2O (300 ml) before NaCl was added until the mixture was saturated. The aqueous phase was extracted with EtOAc (3×500 ml). The combined organic phases were washed with a saturated NaCl solution (300 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product (24.3 g) was dissolved in a little EtAOc at boiling temperature, mixed with petroleum ether (henceforth referred to as PE) (100 ml) and crystallized inside a freezer. The precipitate was filtered by suction and purified by column chromatography (20.7 g crude product, 300 g SiO2, 18×6.5 cm, solvent: toluene/EtOAc 5:1, 4:1, 3:1). Mixed fractions were concentrated under reduced pressure and purified by renewed column chromatography (200 g SiO2, 20×5.3 cm, solvent: toluene/EtOAc 7:1). After concentrating the pooled pure product fractions in a rotating evaporator under reduced pressure, 2-(2,6-dinitrophenyl)ethanol (13.6 g, 64%) was obtained as a yellow solid.