Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH2:10].N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.O>ClCCl.C(OCC)(=O)C>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:10][CH:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:23])=[CH:20][CH:19]=1
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NC1Cc2ccccc2C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of indan-2-ylamine (0.297 g) in dichloromethane (5 ml) were added in turn pyridine (0.23 ml) and 4-fluorobenzoyl chloride (0.26 ml) at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 1 hour, which was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed in turn with hydrochloric acid (1N), aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation under reduced pressure gave a residue, which was triturated with diisopropyl ether to give 4-fluoro-N-(indan-2-yl) benzamide (0.325 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:13][C:14](=[O:17])[CH2:15]Cl)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[K].[O-]CCCC.Cl>CC(OC)(C)C.O.CC(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:11][OH:12])[NH:13][C:14](=[O:17])[CH2:15][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cccc(Br)c1
Agent: CCCC[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CC(C)(C)O
Solvent: COC(C)(C)C
Product: O=C1COCC(CO)(c2cccc(Br)c2)N1

Procedure:
A suspension of N-[1-(3-bromo-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (3.24 g, 10.04 mmol) and 35 ml of t-BuOH was treated with potassium tart-butoxide (1.127 g, 10.04 mmol). The mixture was heated at reflux for 1 h and neutralized with 10 ml of 1N HCl. Water and TBME were added, and the precipitate was filtered off. The organic phase of the filtrate was separated, dried with sodium sulfate and chromatographed on silica gel (EtOAc/MeOH 1-2%) to give the title compound in the form of a colourless solid. TLC (EtOAc/MeOH 1%): Rf=0.23; HPLC: RtH2=2.839 min; 1H-NMR (400 MHz, CD3OD): 7.70 (s, 1H), 7.53-7.47 (m, 2H), 7.35 (t, 1H), 4.17 (s, 2H), 4.08 (d, 1H), 3.98 (d, 1H), 3.91 (d, 1H), 3.87 (d, 1H); MS: 287, 289 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[C:7]([CH2:12][C:13]#[CH:14])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[OH:16][C:17]1[CH:26]=[C:25]([C:14]#[C:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][CH2:4][CH2:3][C:2]3([CH3:15])[CH3:1])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CCc1cccc2c1OCCC2(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCc2cccc3c2OCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.18 g (5.9 mmol) of 3-(4,4-dimethylchroman-8-yl)-1-propyne, 1.60 g (5.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 60 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 332 mg (0.46 mmol) of bis(triphenylphosphine) palladium(II) chloride and 134 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N), and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, an oil, which slowly crystallizes, is obtained and is recrystallized from heptane. 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate is collected in the form of a white solid with a melting point of 92-93° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:18]O>>[CH3:18][O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(B(O)O)cc1
Reaction time: 1 h

Procedure:
A solution of 4-carboxyphenylboronic acid (25 g) and concentrated sulphuric acid (1 ml) in methanol (250 ml) was heated under reflux for 36 hours. Volatile material was removed by evaporation and the residue was dissolved in ethyl acetate (200 ml). Water (100 ml) was added and the mixture was stirred for 1 hour. The organic phase was separated and washed with saturated sodium bicarbonate solution (50 ml), water (100 ml) and saturated sodium chloride solution (50 ml). The solution was dried (MgSO4) and the solvent was removed by evaporation to give 4-methoxycarbonylphenylboronic acid (27.7 g), m.p. 227°-229° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([O:7][C:8]2[C:9]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:10][C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[CH:5][CH:6]=1.[OH-].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:17][S:14]([C:13]1[CH:12]=[C:11]([CH:10]=[C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:8]=1[O:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:18]([O-:20])=[O:19])(=[O:16])=[O:15].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)[O-])cc(N2CCCC2)c1Oc1ccccc1

Procedure:
In a similar manner to Example 9, piretanide can be reacted with benzyltrimethylammonium hydroxide to yield benzyltrimethylammonium 3-aminosulfonyl-4-phenoxy-5-(1-pyrrolidinyl)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CSc1ccc(Br)cc1

Procedure:
The subject compound was prepared starting from 4-bromobenzenethiol and t-butyl bromoacetate in the same manner as Reference example 6-1.
Reaction SMILES: [NH2:1][C:2]1([CH2:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O=S(Cl)Cl.[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[S:26]>>[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]1[S:26][CH2:8][C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[NH:1]1
Reactant: NC1(CO)CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCCC2)CS1

Procedure:
1-Amninocyclohexane-1-carboxylic acid was protected as the benzyloxycarbonylamine according to Method B1a, Step 1. 1-(Benzyloxycarbonylamino)cyclohexane-1-carboxylic acid was reduced to 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane according to Method B1a, Step 2. The carbamate was deprotected according to Method B1a, Step 3 to give 1-amino-1-(hydroxymethyl)cyclohexane. The 2-hydroxyethylamine was sequentially treated with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.5]decane. The thiazolidine was alkylated with isobutyl bromide according to Method D2b to afford 2-(2-methyl-4-nitrophenylimino)-1-isobutyl-3-thia-1-azaspiro[4.5]decane.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[CH3:9].Br[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][CH2:2][CH:3]1[CH2:8][N:7]([C:11]2[CH:16]=[N:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]1[CH3:9]
Reactant: CN1CCNCC1CF
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1CF
Temperature: 25 °C
Yield: 84.5 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 111d (1.6 g, 12.1 mmol), 5-bromo-2-nitropyridine (3.7 g, 18.2 mmol) and cesium carbonate (9.9 g, 30.2 mmol). After bubbling nitrogen through the resulting solution for 30 min, xantphos (700 mg, 0.12 mmol) and tris(dibenzyl-ideneacetone)dipalladium(0) (550 mg, 0.06 mmol) were added, and the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, filtered and concentrated to afford a black solid as the crude product. Then it was purified on silica gel (DCM:MeOH=100:1) to afford 111e as a yellow solid (2.6 g, yield 76%). 1H NMR (500 MHz, MeOD) δ 8.20 (dd, J=12.5 Hz, 2H), 7.51 (dd, J=9.0 Hz, 1H), 4.74-4.54 (m, 2H), 4.03-3.92 (m, 2H), 3.20 (m, 1H), 3.09-2.99 (m, 2H), 2.50 (m, 2H), 2.46 (s, 3H),
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)[N:13]3[CH2:18][CH2:17][NH:16][C:15](=[O:19])[C:14]=23)=[CH:6][CH:5]=1.CI.O.[C:39](=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)[N:13]3[CH2:18][CH2:17][N:16]([CH3:39])[C:15](=[O:19])[C:14]=23)=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCNC3=O)ccc1-n1cnc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCN(C)C3=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (containing mineral oil at 60%, 8 mg) was added to a solution of 1-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one (42 mg) in THF (3 mL), and the reaction solution was stirred at room temperature for 20 minutes. Methyl iodide (20 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 10 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:24]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([NH:1][C:24]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:31])[CH:3]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: O=C1CCCC(=O)O1
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(N)c1
Solvent: CN(C)C=O
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1

Procedure:
In analogy to Example 70.4-6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, glutaric anhydride and Hüinig's base in DMF there was obtained (RS)-4-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid, which was subsequently converted via (RS)-4-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenylcarbamoyl}-butyric acid into (RS)-(E)- and/or -(Z)-4-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenylcarbamoyl)-butyric acid.
Reaction SMILES: C(C1C=C(CC(C)(C)C=O)C=C(C(C)(C)C)C=1O)(C)(C)C.[CH3:22][C:23]([CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([OH:37])=[C:29]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:28]=1)=[O:24]>>[C:33]([C:31]1[CH:32]=[C:27]([CH2:26][CH2:25][CH:23]([OH:24])[CH3:22])[CH:28]=[C:29]([C:38]([CH3:40])([CH3:39])[CH3:41])[C:30]=1[OH:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CC(C)(C=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
If, in Example 1, the 3-(3,5-di-tert.butyl-4-hydroxyphenyl)-2,2-dimethylpropionaldehyde is replaced by an equivalent quantity of methyl-(3,5-di-tert.butyl-4-hydroxyphenylethyl)-ketone, an otherwise identical procedure gives 4-(3,5-di-tert.butyl-4-hydroxyphenyl)-2-butanol of melting point 70° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:16](=[C:21]([NH2:26])[C:22]([F:25])([F:24])[F:23])[C:17]([O:19][CH3:20])=[O:18])(=[O:15])[CH3:14].[F:27][C:28]([F:35])([F:34])[C:29](OCC)=O>CCCCCC.C1COCC1.O>[F:23][C:22]([F:24])([F:25])[C:21]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:13]([OH:15])[CH:14]=[C:29]([C:28]([F:35])([F:34])[F:27])[N:26]=1
Reactant: COC(=O)C(C(C)=O)=C(N)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a flame dried 3-liter, four-necked flask equipped with nitrogen inlet, low temperature thermometer, 500 ml addition funnel and mechanical stirrer is charged 147 ml (1.05 mol) of diisopropylamine and 600 ml of dry tetrahydrofuran. The resulting solution is cooled to -78° C. using an acetone-dry ice bath. To this is slowly added 618 ml (1.05 mol) of 1.7M n-BuLi in hexane at such a rate that the reaction temperature was kept below -60° C. After stirring at -78° C. for 1 hour, a solution of 106 g (0.50 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate from Step 1 in 400 ml of dry THF was added in such a rate that the reaction temperature was kept below -60° C. The reaction mixture turned yellow and a solid suspension formed. After 1 hour of stirring at -78° C., the reaction mixture was treated with 59.5 ml (0.50 mol) of ethyl trifluoroacetate in such rate that the reaction temperature was kept below -60° C. This reaction mixture was left at -78° C. for 1 hour, then warmed to room temperature (the yellow suspension disappeared and a yellow solution was formed) and stirred for 2 hours. The resulting solution was poured into 1 L of H2O and extracted with ether (3×700 ml). The combined ether layers were washed with H2O (2×800 ml) and the combined aqueous layers were acidified with concentrated HCl (pH ~2). The acidified aqueous layer was extracted with CHCl3 (3×1000 ml), dried (MgSO4) and reduced in vacuo affording 120.85 g of a yellow solid. The crude was recrystallized from ether/hexane to give 103.28 g (71%) of pyridine product; mp 62°-75° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].C([Li])CCC.[Si:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>O1CCCC1>[Si:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:40][CH2:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=3[O:12][CH2:13][O:14][CH3:15])([OH:41])[CH2:37][CH2:36]2)=[CH:33][CH:34]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 25.3 %

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 1-bromo-2,4-bis(methoxymethoxy)benzene (277 mg, 1.00 mmol) and anhydrous tetrahydrofuran (5 ml). The stirred solution was cooled to −78° C. and N,N,N′N′-tetramethylethylene diamine (0.32 ml, 2.10 mmol) was added followed by dropwise addition of n-butyl lithium (0.88 ml, 2.10 mmol, 2.40M solution in cyclohexanes). The resulting solution was stirred for 40 min at −78° C., then 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (304 mg, 1.00 mmol) was added via syringe as a solution in anhydrous tetrahydrofuran (2 ml) and the reaction mixture stirred for 30 min at −78° C., then allowed to warm to room temperature over 3 hr. The reaction was quenched with aqueous hydrochloric acid (5 ml, 0.10M), then poured into a separating funnel containing ethyl acetate (50 ml) and water (10 ml). The layers were separated and the aqueous phase extracted with ethyl acetate (3×5 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 3:7, v/v) furnishing the title compound as a white solid (127 mg, 25%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (6H, s), 1.63 (2H, m), 1.84 (2H, m), 1.96 (2H, m), 2.56 (2H, m), 2.70 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 3.85 (1H, s), 5.15 (2H, s), 5.24 (2H, s), 6.68 (1H, dd), 6.73 (2H, d), 6.85 (1H d), 7.05 (2H, d), 7.33 (1H, d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a mixture of methyl 5-(benzyloxy)-2-hydroxybenzoate (10.6 g, 41.1 mmol) and K2CO3 (11.3 g, 82.2 mmol) in DMF (100 mL) was added iodomethane (2.60 mL, 49.3 mmol) drop wise over 5 minutes. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water (400 mL), filtered, and collected the solid. The solid was dissolved in EtOAc (300 mL), washed with water (50 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 5-(benzyloxy)-2-methoxybenzoate (10.4 g, 98%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:5](=[O:6])[CH2:4][CH:3]1[C:7]([O:9]C)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1([CH3:11])[C:5](=[O:6])[CH2:4][CH:3]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C1CC(=O)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(=O)CC1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of methyl 2,2-dimethyl-3-oxocyclobutanecarboxylate (1.0 equiv.) in MeOH (1.1 M) was added aqueous solution of sodium hydroxide (4.48 N, 2.0 equiv.), and the resulting mixture was stirred at 50° C. for 2 h. After reaction completion, the excess MeOH was removed under reduced pressure, and the mixture was extracted with diethyl ether, then the aqueous solution was neutralized with hydrochloride acid (4 N, 2.9 equiv.). The mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum to afford the title product (88% yield) as white solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 12.4 (br, 1H), 3.31-3.23 (m, 1H), 3.17-3.08 (m, 1H), 2.97-2.91 (m, 1H), 1.22 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]([OH:13])(=[O:12])[CH3:11]>[Pd]>[C:10]([OH:13])(=[O:12])[CH3:11].[CH3:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1cccnc1CN

Procedure:
To a solution of 3-methyl-2-cyanopyridine (5 g) in acetic acid was added 10% Pd/C. The Parr shaker bottle was evacuated/H2 purged 3×, and then shaken at 50 psi until starting material was consumed (typically <1 h). The reaction was filtered through diatomaceous earth and concentrated to yield (3-methylpyridin-2-yl)methanamine acetic acid salt which was used without further purification. To the crude salt in THF was added aq 1 M NaOH, followed by BOC2O (2 eq). The reaction was allowed to stir at rt overnight. After ˜16 h, the reaction mixture was transferred to a separatory funnel, diluted with EtOAc, and water, and the layers were separated. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo to give a crude residue which was purified by chromatography on silica gel (EtOAc/hex) to afford tert-butyl ((3-methylpyridin-2-yl)methyl)carbamate. To a solution of the BOC-protected pyridylamine in MeOH was added Nishimura's catalyst. The parr shaker bottle was evacuated/purged with H2 (3×) and then shaken at 50 psi for 24 h. The reaction was filtered through diatomaceous earth, and concentrated in vacuo to give the title compound as a near colorless oil, and was used without further purification. 1H NMR (d6-DMSO, 400 MHz) δ 6.7 (br s, NH), 4.0 (br s, 1H), 2.9-2.7 (m, 3H), 2.6-2.5 (m, 1H), 2.5-2.4 (m, 1H), 1.7-1.6 (br s, 1H), 1.6-1.45 (m, 3H), 1.4 (s, 9H), 1.3-1.2 (m, 1H), 0.8 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>CN(C)C1C=CN=CC=1.ClCCl>[C:12]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A 4-neck 22L round bottom flask equipped with a reflux condenser, mechanical stirrer and thermowell was charged with 5-methoxyindoline (1520 g, ca. 10.2 mol) produced in accordance with Step A, immediately above and dichloromethane (15 L). To the solution was added 4-dimethylaminopyridine (50 g, 0.446 mol), followed by slow addition of acetic anhydride (1051 mL, 11.22 mol, 1.1 equiv, maintaining gentle reflux of the solvent). The reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was diluted with dichloromethane (10 L), then washed with water (15 L) and saturated sodium bicarbonate solution (15 L). The organic layer was dried over sodium sulfate and evaporated in vacuo to a crude solid, which was triturated from heptane (4 L) to afford 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indole (1800 g, 92% yield over two steps). 1H-NMR (CDCl3, 300 MHz) δ 8.13 (d, J=6.3 Hz, 1H), 6.74-6.71 (m, 2 H), 4.05 (t, 2 H), 3.78 (s, 3 H), 3.17 (t, 2 H), 2.21 (s, 3 H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Cl)([O-:9])=[O:8].C(OCC)C>C1(C)C=CC=CC=1>[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(CN2CCOCC2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A solution of morpholine (4.57 mL) in toluene (10 mL) at 5° C. was treated with a solution of 3-nitrobenzyl chloride (4.29 g) in toluene (10 mL). After stirring at 85° C. for 2 hours the reaction mixture was allowed to cool to room temperature and then left to stand overnight. The reaction mixture was treated with diethyl ether (100 mL), then washed three times with water (50 mL), then three times with brine (50 mL), dried over magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica eluting with ethyl acetate to give the title compound (2.86 g) as a white solid, m.p. 48–50° C. 1H NMR [(CDCl3]: δ 8.24 (s, 1H), 8.13 (d, 1H), 7.70 (d, 1H), 7.50 (t, 1H), 3.74 (t, 4H), 3.60 (s, 2H) and 2.48 (s, 4H).