Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[CH2:3][C:4]([CH:6]=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH:26]([O:29][CH2:30]C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)([CH3:28])[CH3:27]>CCC(O)CC>[CH:26]([O:29][CH2:30][CH2:3][C:4]([CH:6]=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])([CH3:28])[CH3:27]
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Reactant: CC(C)OCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CCC(O)CC
Product: CC(C)OCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3.04 g of sodium in 100 ml of 3-pentanol is reacted with 25.0 g of chloromethylcarbonylmethylenetriphenyl phosphorane analogously to the production of isopropoxymethylcarbonylmethylenetriphenyl phosphorane. The title compound is obtained as crystallized oil with a melting point of 66°-70° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C([NH:11][C:12]1[CH:21]=[CH:20][C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][CH:13]=1)(=O)C.Cl.C([O-])(O)=O.[Na+]>CO.O>[NH2:11][C:12]1[CH:21]=[CH:20][C:15]([S:16]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])(=[O:18])=[O:17])=[CH:14][CH:13]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCOCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)(=O)NCCOCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a solution of 3.3 g (31 mmol) of 2-(2-aminoethoxy)ethanol in 30 mL of MeOH was added 7.0 g (30 mmol) of N-acetylsulfanilyl chloride, followed by 3.3 g (33 mmol) of TEA. The reaction mixture was stirred for 30 min at rt and then acidified with 5 mL (60 mmol) of concentrated HCl and stirred at reflux for 75 min. After cooling, the mixture was diluted with 40 mL of water and made basic with solid NaHCO3. MeOH was removed on a rotary evaporator, and the residual aqueous solution was extracted with four 50-mL portions of EtOAc. The combined extracts were dried over Na2CO3, and the solvent was removed on a rotary evaporator to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide as a viscous oil (7.5 g, 96%): 1H NMR (DMSO-d6): δ 2.77 (q, J=6.0 Hz, 2H), 3.30 (t, J=4.9 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.41 (q, J=5.2 Hz, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.89 (s, 2H), 6.57 (d, J=8.7 Hz, 2H) 7.10 (t, J=7.37 (d, J=8.6 Hz, 2H); ESI−MS m/s 259 (M−H)−. To a solution of 0.63 g (2.4 mmol) of 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-benzenesulfonamide in 10 mL of THF was added 0.10 g (2.5 mmol) of 60% sodium hydride. The mixture was stirred for 1 h at rt, 1 mL of DMSO and ˜0.2 mL (˜3 mmol) of methyl iodide were added to the resulting suspension. The reaction mixture was stirred 2 h at rt and then poured into 15 mL of half saturated NaCl solution and extracted with 30 mL of EtOAc. The organic solution was dried with MgSO4 and concentrated on a rotary evaporator. The residue was chromatographed on silica gel with EtOAc to give 4-amino-N-(2-(2-hydroxyethoxy)ethyl)N-methyl-benzenesulfonamide as an oil (0.43 g, 65%): 1H NMR (DMSO-d6): δ 2.59 (s, 3H), 2.96 (t, J=5.9 Hz, 2H), 3.36 (t, J=5.2 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.47 (t, J=5.9 Hz, 2H), 4.55 (t, J=5.4 Hz, 1H), 5.99 (s, 2H), 6.59 (d, J=8.7 Hz, 2H), 7.34 (d, 8.8 Hz, 2H); APCI−MS m/z 297 (M+Na)+. The title compound was prepared from 4-amino-N-(2-(2-hydroxyethoxy)ethyl)-N-methyl-benzenesulfonamide and 8ethoxymethylene-6,8-dihydro-I-thia-3,6-diaza-as-indacen-7-one according to Procedure J: mp 165° C.; 1H NMR (DMSO-d6): δ 2.71 (s, 3H), 3.11 (t, J=5.6 Hz, 2H), 3.37 (t, J=5.0 Hz, 2H), 3.44 (dt, J=5.1, 5.0 Hz, 2H), 3.52 (t, J=5.6 Hz, 2H), 4.56 (brt, J=5.2 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.06 (d, J=12.0 Hz, 1H), 9.25 (s, 1H), 10.91 (s, 1H), 11.16 (d, J=12.0 Hz, 1H); APCI−MS m/z 474 M−. Anal. Calcd for C21H22N4O5S2.H2O: C, 51.21; H,4.91; N, 11.37. Found: C, 51.18; H, 4.88; N, 11.33.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH3:30])[OH:29].Br.[Na].[Cl:33][C:34]1[N:39]=[CH:38][NH:37][C:36]2=[N:40][CH:41]=[CH:42][C:35]=12.C(#N)C>ClCCl>[Cl:33][C:34]1[C:35]2[CH:42]=[CH:41][N:40]([C@@H:13]3[O:16][C@H:17]([CH2:18][O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@H:11]([O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@:12]3([CH3:30])[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: CO[C@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@@]1(C)O
Reactant: Clc1nc[nH]c2nccc1-2
Agent: Br
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound from Step C (9.42 g, 19 mmol) in anhydrous dichloromethane (285 mL) at 0° C. was added HBr (5.7 M in acetic acid, 20 mL, 114 mmol) dropwise. The resulting solution was stirred at 0° C. for 1 h and then at rt for 3 h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×40 mL). The oily residue was dissolved in anhydrous acetonitrile (50 mL) and added to a solution of sodium salt of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine [for preparation, see J. Chem. Soc., 131 (1960)] in acetonitrile [generated in situ from 4-chloro-1H-pyrrolo [2,3-d]pyrimidine (8.76 g, 57 mmol) in anhydrous acetonitrile (1000 mL), and NaH (60% in mineral oil, 2.28 g, 57 mmol), after 4 h of vigorous stirring at room temperature]. The combined mixture was stirred at room temperature for 24 h, and then evaporated to dryness. The residue was suspended in water (250 mL) and extracted with EtOAc (2×500 mL). The combined extracts were washed with brine (300 mL), dried over Na2SO4, filtered and evaporated. The crude product was purified on a silica gel column (10 cm×10 cm) using ethyl acetate/hexane (1:3 and 1:2) as the eluent. Fractions containing the product were combined and evaporated in vacuo to give the desired product (5.05 g) as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1I)=[O:5])[CH3:2].[F:17][C:18]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[C:24]1[CH:23]=[CH:22][C:21]([O:20][C:19]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:18]=2[F:17])=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(F)cc3F)cc2)OC1(C)C
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Product: CCOC(=O)c1c(-c2ccc(Oc3ccc(F)cc3F)cc2)c(C#N)c(CC)n1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in the final step of example E-227 using 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in preparation 38) and 2-[4-(2,4-difluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane. Purify the material by silica gel chromatography (Chromatotron™) eluting with hexane/ethyl acetate 4:1 to provide the final title compound, 4-cyano-5-ethyl-3-[4-(2,4-difluoro-phenoxy)-phenyl]-1-methyl-1H-pyrole-2-carboxylic acid ethyl ester, as a tan solid. Mass spectrum (m/e): 411.1 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.27-7.31 (2H, d), 7.07-7.14 (1H, m), 6.74-6.97 (4H, m), 4.04-4.11 (2H, dd), 3.84-3.88 (3H, s), 2.78-2.89 (2H, dd), 1.23-1.34 (3H, t), 1.00-1.06 (3H, t).
Reaction SMILES: [C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=O)[CH:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].CO.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:16]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2c(cccc2-c2cccc3ccccc23)CC1CC1CCCCC1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: C1=C(CC2CCCCC2)Cc2c1cccc2-c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
24 g (68 mmole) 7-(1-Naphthyl)-2-cyclohexylmethyl-indan-1-one were dissolved in 85 ml toluene in a 500 ml—roundbottom flask equipped with a reflux condenser. 2.82 g (1.1 eq.) sodium borohydride were added. Then 11.8 ml (4.3 eq.) methanol were added at 50° C. and the mixture was stirred for 5 h at 50° C. 2M sulphuric acid was added until the gas evolution ceased. After addition of 100 ml water the layers were separated and the organic layer was washed two times with 2M sulphuric acid and once with a saturated sodium chloride solution. The solvent was evaporated and the crude indanol was dissolved in approx. 250 ml of toluene. After addition of 0.5 g p-toluene sulfonic acid the mixture was heated to reflux using a Dean-Stark-trap until TLC showed complete conversion (90 min). The solution was washed twice with a saturated NaHCO3-solution, once with water and once with a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent afforded 21.65 g (95%) of the desired indene as a slightly offwhite oil. 1H-NMR (400 MHz, CDCl3): δ=7.88 (m, 2H, aromatic), 7.73 (d, 1H, aromatic), 7.55-7.19 (m, 7H, aromatic), 6.10 (s, 1H, C═CH), 3.40 (s, 2H, benzylic) 2.25 (d, 2H CH2Cy), 1.67-0.80 (m, 11H, aliphatic) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:18]1>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:19]2[CH2:20][CH2:21][CH:17]([NH:16][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[C:3]([N:13]([CH3:15])[CH3:14])=[CH:4][C:5]=3[O:11][CH3:12])[CH2:18]2)=[CH:28][CH:27]=1
Reactant: NC1CCN(Cc2ccc(F)cc2)C1
Reactant: COc1cc(N(C)C)c(Cl)cc1C(=O)O
Product: COc1cc(N(C)C)c(Cl)cc1C(=O)NC1CCN(Cc2ccc(F)cc2)C1

Procedure:
Following the procedure set forth in general method A supra using 1.15 g. of 5-chloro-4-dimethylamino-2-methoxybenzoic acid and 1.07 g. of 3-amino-1-(4-fluorobenzyl)-pyrrolidine, 0.9 g. of N-[1-(4-fluorobenzyl)-3-pyrrolidinyl]-5-chloro-4-dimethylamino-2-methoxybenzamide was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:1][C:14]1[C:13]([OH:16])=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=1
Reactant: Cc1ccc(O)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccncc1
Product: Cc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
With cooling with ice, N-bromosuccinimide (18 g) was added to a pyridine (75 ml) solution of 6-methylpyridin-3-ol (10 g), and stirred at room temperature for 4 hours. After further stirred overnight at 50° C., the solvent was evaporated away under reduced pressure. The residue was dissolved in ethyl acetate, and washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water. After dried, the solvent was evaporated away, and the residue was crystallized with chloroform to obtain the entitled compound as a white solid.
Reaction SMILES: [S:1]1[C:5]2[C:6](=O)[NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1Nc2ccccc2Cc2ccsc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccsc1CN2
Yield: 64.2 %

Procedure:
A stirred solution of 2.0 g of 9,10-dihydro-4H-thieno[2,3-c][1]benzazepin-10-one and lithium aluminum hydride (500 mg) in tetrahydrofuran is refluxed for 4 hours. At the end, reaction mixture is carefully quenched with ice cold water and extracted with chloroform. The organic layer is washed well with water and dried over anhydrous Na2SO4, filtered and concentrated. The product is purified by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 1.2 g of the desired product as a bright yellow solid. Mass Spectrum M+ 202.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[C:12]([CH2:14][N:24]([CH3:25])[CH3:23])[CH:11]=[C:10]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C=O)nc(Cc3ccccc3)n2)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2cc(CN(C)C)nc(Cc3ccccc3)n2)cc1
Reaction time: 15 h
Yield: 79 %

Procedure:
To a solution of the product from Step B (0.102 g, 0.35 mmol) in CH2Cl2 (2 mL) was added the Dess-Martin periodinane (0.228, 0.53 mmol). After 30 min, the mixture was diluted satd. aq. NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were dried, concentrated, and filtered through a small plug of SiO2 (25% EtOAc in hexanes). The filtrate was concentrated to give 2-benzyl-6-p-tolyl-pyrimidine-4-carbaldehyde (0.55 g, 54%). To a solution of this aldehyde in CH2Cl2 (3 mL) was added dimethylamine (2 M in THF; 0.15 mL, 0.30 mmol) and NaBH(OAc)3 (0.058 mg, 0.27 mmol). After 15 h, the reaction was diluted with CH2Cl2 and washed with 1 N NaOH. The aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.050 g (79%) of the title compound. MS (ESI): exact mass calcd. for C21H23N3, 317.19; m/z found, 318.4 [M+H]+. 1H NMR (CDCl3): 8.02 (d, J=8.2, 2H), 7.66 (s, 1H), 7.22 (d, J=7.5, 2H), 7.31-7.26 (m, 4H), 7.22-7.18 (m, 1H), 4.33 (s, 2H), 3.58 (s, 2H), 2.41 (s, 3H), 2.32 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](I)[CH3:19]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:18][CH3:19])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nnc(CCNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of [2-(1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (prepared by the protocols outlined in N. A. Delaney, G. C. Rovnyak and M. Loots, European Patent specification EP 449523) (1.0 g, 4.69 mmol) in dry THF (20 ml) is treated with a 60% dispersion of sodium hydride in mineral oil (0.19 g, 4.69 mmol) and stirred at ambient temperature for 10 minutes. Ethyliodide (0.375 ml, 4.69 mmol) is added and the reaction mixture is heated at reflux for 7 hours, then diluted with ethyl acetate and filtered. The filtrate is evaporated and the residue purified by flash silica chromatography (elution 3:2 hexane/ethyl acetate) to afford the titled compound, [2-(2-ethyl-2H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester, eluted first and [2-(1-ethyl-1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester, eluted second.
Reaction SMILES: C(O[N:5]1[CH2:10][CH:9]([CH3:11])[CH2:8][N:7]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:13]=2[Cl:23])[S:6]1(=[O:25])=[O:24])(=O)C.[C:26]([O:29]CC)(=[O:28])[CH3:27].Cl>C1COCC1.CO.O>[Cl:18][C:17]1[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=[C:13]([Cl:23])[C:12]=1[N:7]1[S:6](=[O:24])(=[O:25])[N:5]([CH2:27][C:26]([OH:29])=[O:28])[CH2:10][CH:9]([CH3:11])[CH2:8]1
Reactant: CC(=O)ON1CC(C)CN(c2c(Cl)cc(C(F)(F)F)cc2Cl)S1(=O)=O
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1CN(CC(=O)O)S(=O)(=O)N(c2c(Cl)cc(C(F)(F)F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To ethyl 2-(6-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl acetate (220 mg, 0.45 mmol) in THF (10 mL) and MeOH (10 mL), was dropwisely added LiOH monohydrate (94 mg, 0.45 mmol) in water (3 mL) and agitated for 5 hr at room temperature. After addition of ethyl acetate (30 mL) and water (30 mL), pH of the resultant was adjusted to 3 with 1 N HCl and extracted to obtain the organic layer. The resultant was dried over MgSO4, concentrated under reduced pressure, and crystallized with ethyl acetate (1 mL) and hexane (10 mL), giving the compound of interest (163 mg, 86%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H), 7.64 (s, 1H), 4.53-4.47 (m, 1H), 4.12-3.91 (m, 3H), 3.46-3.42 (m, 1H), 3.26-3.19 (m, 1H), 2.59 (m, 1H), 0.96 (d, 3H, J=6.7 Hz).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@:15]3([CH2:25][C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[Cl:32][C:29]1[N:28]=[CH:27][C:26]([CH2:25][C@@:15]2([O:14][C:12]3[CH:11]=[CH:10][C:9]4[C@H:5]([CH2:4][C:3]([OH:33])=[O:2])[CH2:6][O:7][C:8]=4[CH:13]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:24])[CH2:17][CH2:16]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@]3(Cc4ccc(Cl)nc4)CCc4cccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H]1COc2cc(O[C@@]3(Cc4ccc(Cl)nc4)CCc4cccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-(6-Chloro-pyridin-3-ylmethyl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzo-furan-3-yl}-acetic acid methyl ester (18.6 mg) is dissolved in tetrahydrofuran (4 mL) and 1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with 1N aqueous hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.66 min; Mass spectrum (ESI−): m/z=452/454 (Cl) [M−H]−.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH2:11][NH:12][C:13]([C@:15]12[CH2:50][CH2:49][C@@H:48]([C:51]([CH3:53])=[CH2:52])[C@@H:16]1[C@@H:17]1[C@@:30]([CH3:33])([CH2:31][CH2:32]2)[C@@:29]2([CH3:34])[C@@H:20]([C@:21]3([CH3:47])[C@@H:26]([CH2:27][CH2:28]2)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]2[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1)=[O:14])=O)(C)(C)C.Cl>>[CH3:33][C@:30]12[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:47])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:35])([CH3:36])[C:24]([C:37]3[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][CH:38]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18][C@@H:17]1[C@H:16]1[C@H:48]([C:51]([CH3:53])=[CH2:52])[CH2:49][CH2:50][C@:15]1([C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][NH:8][CH3:6])[CH2:32][CH2:31]2
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCN(C)C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCCNC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C

Procedure:
A vial containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(tert-butoxycarbonyl(methyl)amino)propylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (122 mg, 0.164 mmol) was diluted with HCl (4M in dioxane) (3 mL, 12.00 mmol). The mixture was stirred at rt. After 1.5 h of stirring at rt, LC/MS indicated the reaction was complete. The mixture was concentrated under reduced pressure. The crude product was carried forward to the next step with no additional purification. LCMS: m/e 641.5 (M−H)−, 2.73 min (method 3).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.Cl.[CH3:55][C:56]1([OH:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C)C=O.C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:59]1[CH2:60][CH2:61][C:56]([OH:62])([CH3:55])[CH2:57][CH2:58]1)=[O:30]
Reactant: CC1(O)CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(O)CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (572 mg, 1.51 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (300 mg, 1.01 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (3 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-methylpiperidin-4-ol hydrochloride (154 mg, 1.02 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (3×50 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a gum (94 mg, 23.63% yield); 1H NMR (400.132 MHz, DMSO) δ 1.13 (3H, s), 1.29-1.47 (4H, m), 3.20-3.28 (4H, m), 4.32 (2H, s), 4.41 (1H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.45 (M+H 396.4).
Reaction SMILES: C(=O)(O[CH2:6][C:7](=[CH2:9])[CH3:8])OCC.[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C1C=CC=CC=1)C>[Pd].O1CCCC1>[CH2:8]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C:11]1=[O:17])[C:7](=[CH2:6])[CH3:9]
Reactant: O=C1CCCCC1
Reactant: C=C(C)COC(=O)OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)CC1CCCCC1=O

Procedure:
A mixture containing ethyl methallyl carbonate (1.44 g, 0.010 mole), cyclohexanone (0.98 g, 0.010 mole), 5 percent palladium on carbon (1.0 g), triphenylphosphine (0.20 g, 0.76 mmole), and tetrahyrofuran (15 ml) was refluxed under N2 for 22 hours. Gas chromatographic quantification by means of an internal standard (ethylbenzene) showed 41.6 percent of the cyclohexanone has been consumed and that the desired product, 2-methallylcyclohexanone was formed in 49.2 yield based on unrecovered cyclohexanone. Preparative gas chromatography of the crude mixture gave a pure sample of the product whose structure was confirmed by infrared and nuclear magnetic resonance spectroscopy.