Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](SC)[CH:5]=[CH:6][CH:7]=1.O[O:11][S:12]([O-:14])=O.[K+].[CH3:16]O>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:12]([CH3:16])(=[O:14])=[O:11])[CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1cccc(Br)c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Bromothioanisole was dissolved in methanol (20 ml) and cooled to 0° C. (ice/water bath). A solution of Oxone® (9.22 g) in water (30 ml) was added to this and the resultant cloudy slurry was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and product extracted with dichloromethane. The combined fractions of dichloromethane were washed with brine and dried over anhydrous magnesium sulfate. After filtration, solvent was removed by evaporation under reduced pressure to give the sub-title compound as a solid (1.02 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.Cl.[C:11]([O:15][C:16](=[O:20])[CH2:17][CH2:18][NH2:19])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:19][CH2:18][CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:20])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCNc1ccc(C#N)cn1
Reaction time: 24 h

Procedure:
A solution of 6-chloronicotinonitrile (1.0 g, 7.2 mmol), beta-alanine tert-butyl ester hydrochloride (2.0 g, 11.0 mmol) and DIEA (4.9 mL, 28.9 mmol) in anhydrous dioxane (20 mL) was heated at reflux. After 24 hours, an additional amount of beta-alanine tert-butyl ester hydrochloride (0.5 g, 2.75 mmol) was added. After 24 additional hours at reflux, the reaction mixture was concentrated under reduced pressure. The residue was taken up with EtOAc (50 mL) and washed with water (2×20 mL) and brine (20 mL). The organic layer was dried (MgSO4) and the solvent was removed under reduced pressure. After precipitation from MTBE/pentane, the title compound was obtained as an off-white powder (1.28 g, 72%). HPLC (Method A), Rt: 2.7 min (purity: 99.9%). UPLC/MS, M+(ESI): 248.1, M−(ESI): 246.2. 1H NMR (DMSO-d6, 300 MHz) δ 8.40 (d, J=2.0 Hz, 1H), 7.67 (m, 2H), 6.56 (d, J=8.9 Hz, 1H), 3.50 (td, J=6.8, 6.0 Hz, 2H), 2.48 (t, J=6.8 Hz, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1([CH2:11][CH2:12][CH3:13])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH:2]=[CH2:3]>CO.O=[Pt]=O>[CH2:11]([C:4]1([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH2:12][CH3:13]
Reactant: C=CCC1(CCC)CCCCC1=O
Agent: O=[Pt]=O
Solvent: CO
Product: CCCC1(CCC)CCCCC1=O
Yield: 93 %

Procedure:
2-Allyl-2-propylcyclohexanone (2.96 g, 16.4 mmol) and PtO2 (300 mg) were combined in MeOH (100 mL) and hydrogenated at 1 atm for 4 hrs. The catalyst was filtered off and the solvent evaporated to afford 2.78 g (93%) of 2,2-dipropylcyclohexanone as a colorless liquid. MS (CI) 183 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]2[NH:8][CH:7]=1)=[O:5])[CH3:2].[BH4-].[Li+]>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:15]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:9]2[NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2c1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CNc2c(-c3ccncc3)c(-c3ccc(F)cc3)nn2C1=O
Yield: 39.8 %

Procedure:
To a mixture of 4,7-dihydro-6-ethoxycarbonyl-2-(4-fluorophenyl)-3-(pyridin-4-yl)-7-oxopyrazolo[1,5-a]pyrimidine (100 mg) in tetrahydrofuran (4 ml) was added lithium borohydride (2 mole in tetrahydrofuran, 0.26 ml) at room temperature and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was quenched with an aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried and concentrated in vacuo. The residue was crystallized from ethanol to give 6-ethoxycarbonyl-2-(4-fluorophenyl)-7-oxo-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (40 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[CH:13]=1)=[CH:6]2.B(Br)(Br)Br>>[OH:18][C:14]1[CH:13]=[C:12]([C:7]2[NH:8][C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=3)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(-c2cc3cc(OC)ccc3[nH]2)c1
Agent: BrB(Br)Br
Product: Oc1cccc(-c2cc3cc(O)ccc3[nH]2)c1
Yield: 76 %

Procedure:
The compound is prepared by reaction of 5-methoxy-2-(3-methoxyphenyl)-1H-indole (89 mg, 0.35 mmol, 1 eq) with boron tribromide (2.1 ml, 2.1 mmol, 6 eq) according to method G. Purification by preparative thin-layer chromatography with hexane/ethyl acetate 4/6 yields the desired product in a yield of 76%, 60 mg.
Reaction SMILES: [NH2:1][C:2]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO>>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]([CH2:10][CH3:11])[CH2:12][CH3:13])[C:3]=1[C:7]#[N:8]
Reactant: CCN(CC)C(N)=C(C#N)C(N)=S
Agent: OO
Product: CCN(CC)c1nsc(N)c1C#N
Yield: 76.9 %

Procedure:
Using the procedure of Example I, part F, 54.5 g of 3-amino-2-cyano-3-(diethylamino)propenethioamide were oxidized with 41 ml of 30% hydrogen peroxide to give 41.5 g of white 5-amino-4-cyano-3-(diethylamino)isothiazole, m.p. 87°-88°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl[C:14](Cl)(Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]>C(Cl)(Cl)Cl>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:14](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Clc1ccccc1C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N=C(Nc2ccc(C(=O)OCC)cc2)c2ccccc2Cl)cc1

Procedure:
N,N'-Bis(4-ethoxycarbonylphenyl)-2-chlorobenzamidine (10) was prepared from ethyl 4-aminobenzoate and α,α,α,2-tetrachlorotoluene; tan solid: mp 98°-108° C. 1H-NMR (CDCl3) 8.3-6.4 (m, 13H), 4.2 (q, 4H, J=7 Hz); IR (CHCl3) 3360, 1695, 1600, 1580; MS (m/e) 450, 452 (M+), 286 (base).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[C].[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH2:12][CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])=[O:24])=[CH:20][CH:19]=1
Reactant: CN(CCCNC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCCNC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
The compound (1.27 g, 3.78 mmol) obtained in Example 73b was dissolved in 40 mL of methanol, 100 mg of 10% palladium-carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through celite, and then the solvent of the filtrate was evaporated under reduced pressure to give the title compound (1.14 g; yield, 98%) as a colorless oily substance.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:43])[CH2:17][CH2:18][N:19]([CH2:24][CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[C:33]([O:35]CC1C=CC=CC=1)=[O:34])=[O:27])[CH2:20][CH:21]1[CH2:23][CH2:22]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)(C)C.[Pd]>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][CH2:24][N:19]([CH2:20][CH:21]1[CH2:22][CH2:23]1)[CH2:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:43])([OH:35])=[O:34]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)CC1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)O)CC1CC1
Yield: 101 %

Procedure:
A solution of 220 mg (0.37 mmol) (R)-1-[3-[[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-cyclopropylmethyl-amino]-propionyl]-pyrrolidine-2-carboxylic acid benzyl ester in 20 ml isopropanol was stirred with 10 mg 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, concentration in vacuo afforded 153 mg (100%) of the title compound as a yellow solid. MS m/e (%): 408 ([M−H]−, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:28][C:14]4([C:29]5[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=5)[CH2:15][C:16]([C:19]5[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=5)([CH2:18][C:12]([C:38]5[CH:43]=[CH:42][C:41]([N+:44]([O-])=O)=[CH:40][CH:39]=5)([CH2:13]4)[CH2:11]2)[CH2:17]3)=[CH:6][CH:5]=1)([O-])=O.Cl.Cl[Sn]Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:11][C:12]4([C:38]5[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=5)[CH2:18][C:16]([C:19]5[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=5)([CH2:15][C:14]([C:29]5[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=5)([CH2:13]4)[CH2:28]2)[CH2:17]3)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C23CC4(c5ccc([N+](=O)[O-])cc5)CC(c5ccc([N+](=O)[O-])cc5)(C2)CC(c2ccc([N+](=O)[O-])cc2)(C3)C4)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C23CC4(c5ccc(N)cc5)CC(c5ccc(N)cc5)(C2)CC(c2ccc(N)cc2)(C3)C4)cc1

Procedure:
To 1,3,5,7-tetra(p-nitrophenyl)adamantane (0.62 g, 1 mmol) was added 75 mL of ethyl alcohol followed by 15 mL of concentrated hydrochloric acid. Stannous chloride (SnCl2 --2H2O, 4.1 g, 15 mmol), was added to the mixture. After refluxing for 48 hours, the solvent was evaporated and 15 mL of water was added. The aqueous solution was made basic by adding 3M NaOH and was extracted four times with 50 mL of THF. The solvent was evaporated and crude 1,3,5,7-tetra(4-aminophenyl)adamantane was collected (0.5 g, mmol, >90%). 1H NMR (DMSO-d6, 360 MHz): of 1,3,5,7-tetra(4-aminophenyl)adamantane δ1.82 (s 12H), 4.79 (s 8H), 6.50, 6.52, 7.11, 7.13 (AA'BB', 16H). 13C NMR 37.77 (CH2), 47.64 (C--Ph--NH2), 113.65, 125.18, 137.60, 146.12 (Ph--NH2).
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][CH2:5][NH:6][C:7](=[O:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][CH2:5][C:4]#[C:3][CH2:2][NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)=[O:27])=[CH:14][CH:15]=1
Reactant: NCC#CCNC(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)NCC#CCNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,6-bis-(4-fluoro-phenyl)-hexanoic acid (4-amino-but-2-ynyl)-amide (0.69 g, 1.86 mmol) in dry CH2Cl2 (40 ml) was added 4-chlorobenzoic acid (0.29 g, 1.86 mmol) under nitrogen. To the reaction was added EDC (0.71 g, 3.72 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (30 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (20:1) to give a desired product in good yield.
Reaction SMILES: [Na].[CH3:2][C:3]1([CH3:11])[CH2:7][CH2:6][CH:5]([CH:8]=O)[C:4]1=O.[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13].N1CCCCC1.C(O)(=O)C>O>[OH:16][C:15]1[N:17]=[C:4]2[C:3]([CH3:11])([CH3:2])[CH2:7][CH2:6][C:5]2=[CH:8][C:14]=1[C:12]#[N:13]
Reactant: N#CCC(N)=O
Reactant: CC1(C)CCC(C=O)C1=O
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CC1(C)CCc2cc(C#N)c(O)nc21
Temperature: 100 °C
Reaction time: 26 h
Yield: 13.8 %

Procedure:
To a solution of 3,3-dimethyl-2-oxocyclopentanecarbaldehyde sodium salt (5 g, 30.9 mmol) in water (10 mL) was added cyanoacetamide (2.5 g, 30.9 mmol), piperidine (2.6 g, 30.9 mmol in 10 mL water) and acetic acid (1 mL) in that order. The reaction mixture was stirred at 100° C. for about 26 h and then cooled to a temperature of about 20-35° C. The reaction mass was adjusted to pH value of about 6 and was then filtered off to obtain a crude product. The crude product was purified by column chromatography (60-120 mesh silica gel) with 10% ethyl acetate in petroleum ether as the eluent to obtain the desired product as a brown liquid (0.8 g).
Reaction SMILES: O.O.[Sn](Cl)Cl.[N:6]1([C:11]2[CH:12]=[CH:13][C:14]3[C:20](=[O:21])[C:19]4[CH:22]=[CH:23][C:24]([N+:26]([O-])=O)=[CH:25][C:18]=4[CH2:17][O:16][C:15]=3[CH:29]=2)[CH:10]=[N:9][N:8]=[N:7]1>C(O)C>[NH2:26][C:24]1[CH:23]=[CH:22][C:19]2[C:20](=[O:21])[C:14]3[CH:13]=[CH:12][C:11]([N:6]4[CH:10]=[N:9][N:8]=[N:7]4)=[CH:29][C:15]=3[O:16][CH2:17][C:18]=2[CH:25]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2COc2cc(-n3cnnn3)ccc21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)COc1cc(-n3cnnn3)ccc1C2=O

Procedure:
In accordance with general method Y, 1.50 g (6.66 mmol) of tin(II) chloride dihydrate are dissolved in 10 ml of ethanol, and 0.50 g (1.54 mmol) of (20) is added.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)C(C)C)C.[CH2:14]=[C:15]([CH2:18][CH3:19])[CH2:16][OH:17]>C1COCC1>[CH3:1][O:2][CH2:3][O:17][CH2:16][C:15]([CH2:18][CH3:19])=[CH2:14]
Reactant: C=C(CC)CO
Reactant: COCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CC)COCOC
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.4 %

Procedure:
Chloromethyl methyl ether (103.4 ml, 1363 mmol) and N-ethyldiisopropylamine (247.2 ml, 1419 mmol) were added to a solution of 2-methylene-1-butanol (65.1 g, 757 mmol) prepared in Reference Example 205 in THF (750 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-1-butene (98 g, quantitative) as a colorless oil.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].C[CH2:17][N:18]([CH2:23][O:24]C)[Si](C)(C)C.F[C:27](F)(F)C(O)=O>C(Cl)Cl>[C:23](=[O:24])([O-:2])[NH2:18].[CH3:17][N:18]1[CH2:23][CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:13])([F:14])[F:15])[CH:4]([N+:1]([O-:3])=[O:2])[CH2:27]1
Reactant: O=[N+]([O-])/C=C/c1ccccc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(COC)[Si](C)(C)C
Solvent: ClCCl
Product: CN1CC(c2ccccc2C(F)(F)F)C([N+](=O)[O-])C1
Product: NC(=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(E)-1-(2-Nitrovinyl)-2-(trifluoromethyl)benzene (230.8 mg, 1.063 mmol) and methyl-methoxymethyltrimethylsilanyl-methylamine (206 mg, 1.275 mmol) was dissolved in DCM (4 mL) and cooled to 0° C. under N2. Trifluoroacetic acid (8.19 μL, 0.106 mmol) was then added and the reaction mixture was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with DCM and washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo while loading onto silica gel. The residue was purified by flash chromatography (7-60% EtOAc-hexanes) to give (3S and R,4R and S)-1-methyl-3-nitro-4-(2-(trifluoromethyl)phenyl) pyrrolidine. 1H NMR (500 MHz, DMSO-d6) δ 7.84-7.65 (m, 3H), 7.5 (t, J=7.4 Hz, 1H), 5.40-5.34 (m, 1H), 4.18-4.10 (m, 1H), 3.40 (dd, J=3.0, 11.3 Hz, 1H), 3.20 (t, J=8.4 Hz, 1H), 3.10-3.04 (m, 1H), 2.40-2.28 (m, 1H), 2.3 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22](OCC)=[O:23])=[CH:4][N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH2:22][OH:23])=[CH:4][N:5]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2ccccc2)c(-c2ccccc2)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(CO)c(F)c1-c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution (10 mL) of ethyl 4-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (60 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (0.5 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3) to give the title compound as a colorless oil (yield 40 mg, 75%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=[CH:27][N+:24]([O-:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2ccc(Cc3ccccc3)cc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: O=[N+]([O-])C=Cc1c[nH]c2ccc(Cc3ccccc3)cc12
Yield: 34 %

Procedure:
The aidehyde 5-benzyl-3-formylindole (0.15 g, 0.6 mmol), nitromethane (0.9 ml) and ammonium acetate (0.05 g, 0.7 mmol) were heated gently under reflux for 0.5 h. On cooling, dark ruby-red crystals slowly separated. Crystallization from methanol gave 0.06 g (34%) of 5-benzyl-3-(2-nitroethenyl)indole as orange crystals.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([C:34]([F:45])([F:44])[F:33])[CH:40]=2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25.9 %

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol), 3-(trifluoromethyl)phenylboronic acid (165 mg, 869 μmol; 4 eq.), copper(II) acetate (158 mg, 869 μmol; 4 eq.) and 4 Å molecular sieve (500 mg) were initially charged in dichloromethane (5 ml), pyridine (281 μl; 16 eq.) and triethylamine (121 μl; 4 eq.) were added and the mixture was subsequently stirred at RT for 20 h. The reaction mixture was then filtered through kieselguhr which was then washed repeatedly with methanol, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Column: Gromsil, C-18 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (34 mg, 26% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@H:16]([NH:18][C:19]([C:21]3[NH:25][C:24]([CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:23][CH:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl>CCO>[NH2:27][CH2:26][C:24]1[NH:25][C:21]([C:19]([NH:18][C@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)=[O:20])=[CH:22][N:23]=1
Reactant: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(CNC(=O)OC(C)(C)C)[nH]1
Agent: Cl
Solvent: CCO
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(CN)[nH]1
Yield: 64.5 %

Procedure:
(R)-tert-butyl (5-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-imidazol-2-yl)methylcarbamate (0.42 mmol) was stirred with 10% HCl (g) in EtOH (30 ml) overnight. Solvent was evaporated and the residue was taken up in water (50 ml), washed with DCM (3×30 ml) and made strongly alkaline by adding 2 M NaOH solution. The water phase was extracted with DCM (3×50 ml) and combined organic phases were dried over Na2SO4 and evaporated to yield 104 mg (65%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.08 (d, 3H), 3.73 (s, 2H), 4.27 (dd, 1H), 4.32-4.48 (m, 2H), 6.95 (d, 1H), 7.44 (s, 1H), 7.83 (d, 1H), 7.94-8.03 (m, 2H), 8.07 (d, 1H), 8.10 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][C:12](Cl)=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]2[C:3]=1[CH2:10][CH2:11][C:12]2=[O:13].[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(Cl)CCCl
Product: Cc1ccccc1
Product: O=C1CCc2c(F)ccc(O)c21
Yield: 86.1 %

Procedure:
4-Fluoro-7-hydroxy-indan-1-one is prepared in analogy to the non-fluorinated compound by the process of S. Wagatsuma et al. [Org. Prep. Proced. Int., 5(2), 1973, 65-70] in two steps: 1. esterification of 4-fluorophenol and 3-chloropropionyl chloride by refluxing both components in toluene (yield: 86.1%, b.p: 150° C./30 mm); 2. heating the ester in the presence of AlCl3 (yield: 53.9%, m.p.: 87° C.).