Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([O:28][C:29](=[O:31])[CH3:30])[CH:25](OC(=O)C)[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([O:28][C:29](=[O:31])[CH3:30])[C@H:25]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (4.42 g, 24.0 mmol) in ACN (20 mL) was added BSA (14.8 mL, 60.0 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hr to form a clear solution. After the solution was cooled to room temperature, [(2S,4R)-4,5-diacetoxytetrahydrofuran-2-yl]methyl benzoate (CAS #: 4613-71-2, Cat.#: MD04725, commercially available from Carbosynth Limited, 6.45 g, 20.0 mmol) and TMSOTf (5.5 mL, 30.0 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford 5.7 g of [(2S,4R,5R)-4-acetoxy-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)tetrahydrofuran-2-yl]methyl benzoate (compound 38a) as a light yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([NH2:17])[C:10](=[CH:15][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12]>N1C=CC=CC=1>[CH3:1][S:2]([NH:17][C:9]1[C:10](=[CH:15][CH:16]=[C:7]([F:6])[CH:8]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(F)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.68 g) was added dropwise to a stirred solution of methyl 4-fluoroanthranilate (1 g) in pyridine (dried over 4A sieves, 10 ml) at 0°-5°. After 18 hours at room temperature, the mixture was cooled to 0°-5° and further methanesulphonyl chloride (0.68 g) was added dropwise. The mixture was stirred for 24 hours at room temperature. Aqueous work up and recrystallisation from ethanol gave methyl N-(methylsulphonyl)-4-fluoroanthranilate, mp 115.5°-116.5°. (Compound 19).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19](#[N:23])[CH:20]([CH3:22])[CH3:21].Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:26][Si:25]([CH3:28])([CH3:27])[C:20]([CH3:22])([CH3:21])[C:19]#[N:23]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)C#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C#N)[Si](C)(C)C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
2-(Trimethylsilyl)isobutyronitrile was prepared by the following procedure. To a stirred solution of 30.2 g (0.29 mole) of diisopropylamine in 220 ml of THF under argon was added at 0°-5° 184 ml of 1.58 M n-butyl lithium/hexane at a rate such that the temperature did not exceed 6°. After 15 min. 20 g (0.29 mole) of isobutyronitrile was added at 0°-5°. After 20 min., 47.3 g (0.44 mole) of chlorotrimethylsilane was added. After standing 18 h at room temperature, the mixture was filtered under argon and the filtrate was evaporated in vacuo to a solid which was extracted with ether and filtered. The filtrate was evaporated in vacuo to give 30.51 g (74%) of 2-(trimethysilyl)isobutyronitrile as a pale yellow watersensitive solid. Anal. Calcd. for C7H15NS: C, 59.50; H, 10.70; N, 9.92. Found: C, 59.60; H, 11.07; N, 9.74. I.R. (CCl4): 2220 cm-1 (C≡N), 847 cm-1, 1255 cm-1 (SiMe3). NMR (90 MHz): δ0.22 (9H, SiCH3); δ1.35 (6H, CCH3).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][Cl:35].O>CN(C=O)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][CH2:32][CH2:33][CH2:34][Cl:35])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 57.3 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (0.5 g, 1.66 mmol) in dry DMF (5 mL) is added potassium carbonate (1.15 g, 8.3 mmol) and 1-bromo-4-chlorobutane (1.4 g, 8.3 mmol). The mixture is heated at 85° C., under argon, for 4 h. The mixture is then cooled to room temperature and water (50 mL) is added. The mixture is transferred to a separatory funnel and partitioned between water and ether. The ether layer is washed with water (50 mL) then dried over anhydrous sodium sulfate. The ether filtrates are then concentrated. Column chromatography (50 mL silica) using hexanes followed by hexanes/methylene chloride (1:1) gave 0.373 g (57%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:20])=[C:15]([CH:19]=2)[C:16]([OH:18])=O)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][N:54]=1>C(Cl)Cl>[NH2:52][C:53]1[N:54]=[CH:55][C:56]([NH:59][C:16](=[O:18])[C:15]2[CH:19]=[C:11]([CH:12]=[CH:13][C:14]=2[CH3:20])[C:9]([NH:8][CH2:7][CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:10])=[CH:57][CH:58]=1
Reactant: Nc1ccc(N)nc1
Reactant: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)NCCC2CCCC2)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a RBF was charged 5-((2-cyclopentylethyl)carbamoyl)-2-methylbenzoic acid (0.25 g, 0.91 mmol), DCM (3 ml), n,n-diisopropylethylamine (0.6 ml, 3.5 mmol), HOBt (0.14 g, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.1 mmol), and 2,5-diaminopyridine (0.1 g, 0.91 mmol) in that order. This mixture was stirred at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 mL). The precipitate formed was collected, washed with water, dried in a vacuum oven overnight to give N3-(6-aminopyridin-3-yl)-N1-(2-cyclopentylethyl)-4-methylisophthalamide as a purple solid.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:11])([CH3:10])[CH3:9])=[O:4].ClC1C=CC=C(C(OO)=O)C=1.C[Si]([C:35]#[N:36])(C)C.CN(C)C(Cl)=O>C(OCC)(=O)C.O>[CH3:1][C:2]([CH3:19])([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:35]#[N:36])[CH:14]=1)[C:3]([O:5][CH2:6][CH2:7][Si:8]([CH3:9])([CH3:10])[CH3:11])=[O:4]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(Cc1ccncc1)C(=O)OCC[Si](C)(C)C
Agent: CN(C)C(=O)Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(Cc1ccnc(C#N)c1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.9 %

Procedure:
2-(Trimethylsilyl)ethyl 2,2-dimethyl-3-(4-pyridyl)propionate (0.77 g, 2.8 mmol) was dissolved in ethyl acetate (4 ml), and 3-chloroperbenzoic acid (ca. 77%, 0.68 g, 3.0 mmol) was added thereto. The reaction mixture was stirred at room temperature for 5 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with ethyl acetate-ethanol (4:1, v/v) were collected and concentrated. The residue was dissolved in acetonitrile (6 ml), and trimethylsilyl cyanide (0.49 g, 4.9 mmol) and N,N-dimethylcarbamoyl chloride(0.45 g, 4.2 mmol) were added thereto. The reaction mixture was stirred at room temperature for 14 hrs and combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution, 1 N hydrochloric acid and saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (30 g) column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected and concentrated to give the titled compound (0.69 g, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7](F)[CH:6]=1)[CH3:2].[CH3:16][NH2:17]>C1COCC1.CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:17][CH3:16])[CH:6]=1)[CH3:2]
Reactant: CN
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NC)c1

Procedure:
3-Methylamino-4-nitro-benzoic acid ethyl ester (2.8 g) was prepared by following General Procedure A starting from 3-fluoro-4-nitro-benzoic acid ethyl ester (3 g) and 2 M methylamine in THF (15 mL) in DMF (15 mL).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>O1CCCC1.O>[OH:16][N:15]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
A solution of methyl 4-formyl-2-methylbenzoate (1.3 g) in tetrahydrofuran (50 mL) was added dropwise to a solution of hydroxylamine hydrochloride (1.0 g), sodium acetate (1.2 g) in tetrahydrofuran (50 mL) and water (50 mL) under ice cooling, and after finishing the dropwise addition, the mixture was stirred for one hour at room temperature. The reaction mixture was diluted with water and then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of methyl 4-[(hydroxyimino)methyl]-2-methylbenzoate (1.3 g).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][CH:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:19]([CH:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]3)[CH3:18])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1ccc(NC(=O)NCC2CC2)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To a stirred mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (4.99 mmol, 1.170 g), tert-butyl 3-(methylamino)pyrrolidine-1-carboxylate (4.99 mmol, 1 g) and triethylamine (11.98 mmol, 1.670 mL, 1.213 g) in dichloromethane (50 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (5.99 mmol, 1.149 g). The reaction was stirred for 20 hours. Chromatography on silica (eluting with a gradient of dichloromethane to ethyl acetate) gave the intermediate tert-butyl 3-(4-(3-(cyclopropylmethyl)ureido)-N-methylbenzamido)-pyrrolidine-1-carboxylate (2 g).
Reaction SMILES: [CH2:1]([CH2:11]C(=O)C)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].ClCC([O:19][CH2:20][CH3:21])=O.[O-][CH2:23]C.[Na+].[OH-].[K+]>CO.C(O)(=O)C.O>[CH3:23][CH:21]([CH2:11][CH2:1][CH:2]=[C:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[CH:20]=[O:19]
Reactant: CCOC(=O)CCl
Reactant: CC(=O)CC/C=C(\C)CCC=C(C)C
Reactant: CC[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)=CCCC(C)=CCCC(C)C=O
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a mixture of geranylacetone (171 g) and ethyl monochloroacetate (141 g) at -10°C in the nitrogen stream, sodium ethoxide (71 g) is portionwise added, and the resultant mixture is stirred for 6 hours. A solution of potassium hydroxide (99 g) in methanol (560 ml) is added thereto, and stirring is continued for 2 hours. The reaction mixture is poured into water and skaken with petroleum ether. The water layer is neutralized with acetic acid and extracted with ether. The ether extract is washed with water and dried. After evaporation of the ether, the residual material is distilled under reduced pressure to give 2,6,10-trimethyl-5,9-undecadienal (135 g) as a pale yellow oil. B.P. 100° to 103°C/0.4 mm Hg. Yield, 73.6%. IR: 2680, 1720 cm-1 (CHO).
Reaction SMILES: C([CH2:3][C:4](=O)[CH2:5][CH:6](Cl)[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1)C.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CN(C)C(=[O:33])C>>[Br:21][C:22]1[CH:23]=[C:24]([N:25]2[CH:6]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=3)[CH2:5][CH2:4][C:3]2=[O:33])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)N(C)C
Reactant: CCCC(=O)CC(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: Nc1cccc(Br)c1
Product: O=C1CCC(c2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)N1c1cccc(Br)c1
Temperature: 120 °C
Yield: 28 %

Procedure:
Ethyl 4-chloro-4-(3,4-dinitrophenyl)butanone (366.3 mg, 1.2 mmol.), 3-bromoaniline (220 mg, 1.3 mmol.) and N,N-dimethylacetamide (0.3 mL) were combined and heated to 120° C. over 17 hours under a nitrogen atmosphere. The mixture was then cooled to room temperature and partitioned with ethyl acetate and water. The organic layer was washed twice with additional water, then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by purification of the residue by silica gel flash chromatography (100% ethyl acetate eluent) gave 1-(3-bromophenyl)-5-(3,4-dinitrophenyl)pyrrolidin-2-one (132 mg, 28% yield) as an amorphous residue. The material thus obtained is contaminated by variable amounts of 5-(3,4-dinitrophenyl)dihydrofuran-2(3H)-one as a side product and is carried forward without further purification. MS (EI) for C16H12N3O5Br: 407 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:13]C1C=CC=CC=1.CC1C=C(C(F)(C(F)(F)F)C(F)(F)F)C=C(C)C=1N>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:13])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Agent: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Product: NC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
3-nitro-benzoyl chloride was reacted with an aniline, that is 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamine, to form a 3-nitro-benzamide, that is 3-nitro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide, and c) the 3-nitro-benzamide, that is 3-nitro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide, was reduced to afford the desired 3-amino-benzamide, that is 3-amino-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide. Further 3-amino-benzamides were made, for example, by using a substituted 3-nitro-benzoic acid, such as 2-fluoro-3-nitro-benzoic acid, in step a) and/or a different aniline, such as 2-ethyl-6-methyl-4-(1,2,2,2-tetrafluoro-1-trifluoro-methyl-ethyl)-phenylamine, in step b). Whilst this three step synthesis gives satisfactory results in the laboratory a shorter route to 3-amino-benzamides is required if the carbamate insecticides or bisamide insecticides are to be manufactured on a commercial scale.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1([CH3:24])[CH2:15][C:14]2[NH:13][CH:12]=[C:11]([CH2:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:10]=2[CH2:9][CH2:8]1.CN([CH:28]=[O:29])C>>[CH2:20]([N:19]([CH2:22][CH3:23])[CH2:18][CH2:17][CH2:16][C:11]1[C:10]2[CH2:9][CH2:8][C:7]([CH3:6])([CH3:24])[CH2:15][C:14]=2[NH:13][C:12]=1[CH:28]=[O:29])[CH3:21]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCCc1c[nH]c2c1CCC(C)(C)C2
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCCc1c(C=O)[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
POCl3 (0.35 mL, 3.74 mmol) was added dropwise to DMF (0.8 mL, 10.3 mmol) at −5° C. After stirring at room temperature for 30 min, the mixture was cooled to −5° C. A solution of [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-diethylamine (0.9 g, 3.4 mmol) in DMF (2 mL) was then added dropwise. The mixture was stirred at room temperature for 3 hours and then quenched with ice, followed by 10 N KOH to adjust pH to 10-11. After stirring at room temperature for 1 hour, the mixture was extracted with EtOAc, washed with brine, dried and concentrated to give 0.55 g 3-(3-diethylaminopropyl)-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:12]([OH:24])[C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:8]1([C:12]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)=[O:24])[CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1ccc(C(O)C2CCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(=O)C2CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
Trifluoroacetic acid (613 mg, 5.38 mmol) was added dropwise to a 0° C. solution of ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (700 mg, 3 mmol) in dichloromethane (10 mL). Then Dess-Martin periodinane (2.03 g, 4.78 mmol) was added and the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(cyclobutanecarbonyl)benzoate (540 mg, 78%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 8.04 (d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 3.90-3.99 (m, 1H), 2.20-2.40 (m, 4H), 2.00-2.09 (m, 1H), 1.81-1.90 (m, 1H), 1.34 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:3][CH2:2]1.[Si:34]([O:41][C@@H:42]([C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:77])[CH3:76])[C@@H:47]([O:66][Si:67]([C:70]([CH3:73])([CH3:72])[CH3:71])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:49][O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:43][NH:44][CH3:45])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:33])[NH:6][C:7]2[CH:31]=[CH:30][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:29]=[CH:28][C:24]([C:25]([N:44]([CH3:45])[CH2:43][C@@H:42]([O:41][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[C@H:46]([O:74][Si:75]([C:78]([CH3:81])([CH3:80])[CH3:79])([CH3:76])[CH3:77])[C@@H:47]([O:66][Si:67]([C:70]([CH3:71])([CH3:72])[CH3:73])([CH3:69])[CH3:68])[C@@H:48]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:60])[CH3:61])[CH2:49][O:50][Si:51]([C:54]([CH3:55])([CH3:56])[CH3:57])([CH3:53])[CH3:52])=[O:27])=[CH:23][N:22]=5)[S:20][C:13]=34)=[C:9]([F:32])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CNC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)O)cn4)sc23)c(F)c1)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
To a solution of acid 225 (220 mg, 0.474 mmol, scheme 54), amine 242 (309 mg, 0.474 mmol) and DIPEA (0.331 mL, 1.895 mmol) in DMF (5 mL) was added HATU reagent (270 mg, 0.710 mmol). The mixture was stirred overnight at room temperature then partitioned between ethyl acetate and water. The organic layer was collected, washed with water, 1M NaOH, and brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by Biotage (MeOH/DCM, 0-15%, SNAP 10 g cartridge) to afford title compound 243 (250 mg, 0.254 mmol, 54% yield) as a white solid. MS: 985.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(O)=O.[H][H]>CO>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(F)cc1N
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-5-methoxy-4-nitrobenzoic acid (10 g, 46 mmol), HOAc (50 mL) and MeOH (50 mL) was hydrogenated using a hydrogen balloon overnight. The solution was then filtered through celite and concentrated to a residue, which was triturated with ether and ethyl acetate. The solid was filtered and dried to give the product as light yellow powder (8.3 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3 H) 5.88 (br s, 2 H) 6.36 (d, J=16 Hz, 1 H) 7.13 (d, J=8 Hz, 1 H) 12.32 (br s, 1 H). [M+H] calc'd for C8H8FNO3, 186; found 186.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[C:14](\[C:12]#[N:13])/[C:15]([O:17][CH2:18][CH3:19])=[O:16])/[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)/C(C#N)=C1\CCc2cc(Cl)ccc21
Yield: 68 %

Procedure:
A mixture of 5-chloro-2,3-dihydro-1H-inden-1-one (150 g, 0.9 mol, commercially available) and ethyl cyanoacetate (125 g, 1.1 mol), ammonium acetate (150 g, 1.94 mmol) and glacial acetic acid (500 mL) in benzene (1 L) was refluxed with a Dean Stark water trap for 22 h. Then benzene was partially removed under vacuum, the residue was filtered and the solid obtain was crystallized from ethanol to give the title compound (161 g, y=68%).