Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CS(O[CH2:12][CH2:13][C:14]1([CH2:20][CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)(=O)=O.O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[C:36]([Si:23]([O:22][CH2:21][CH2:20][C:14]1([CH2:13][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](OCCC1(CCOS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC1(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCCCC1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
After suspending lithium aluminum hydride (0.30 g, 7.80 mmol) in tetrahydrofuran (15 mL), a solution of 2-[1-(2-tert-butyldiphenylsiloxyethyl)cyclohexyl]ethyl methanesulfonate (3.97 g, 7.80 mmol) in tetrahydrofuran (10 mL) was added dropwise at room temperature over a period of 10 minutes. After stirring for an additional 10 minutes, the mixture was heated to reflux for 45 minutes. Water (0.30 mL), 15% aqueous sodium hydroxide (0.30 mL) and water (0.90 mL) were added dropwise in that order while cooling on ice, diethyl ether (25 mL) was added and the mixture was stirred for 16 hours, and then celite was added and stirring was continued for 1 hour prior to filtration. The filtrate was concentrated under reduced pressure to obtain the title compound as a colorless oil (3.02 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]1[C@@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.C(Cl)Cl.CO>O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:16]3[C@@H:17]4[C@H:22]([C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3ccccc3CC[C@@H]21
Yield: 31 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 31% of theory; TLC: rf=0.40 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=332 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.32-1.46 (m, 1H), 1.53-1.76 (m, 2H), 2.14-2.24 (m, 1H), 2.30-2.43 (m, 1H), ca. 2.49-2.56 superimposed by D3CSOCHD2 signal (m, 1H), 2.77-2.93 (m, 2H), 3.03-3.13 (m, 1H), ca. 3.25-3.34 superimposed by H2O signal (m, 1H), 3.34-3.43 (m, 1H), 3.67-3.76 (m, 1H), 7.07-7.19 (m, 3H), 7.26-7.32 (m, 2H), 7.59-7.70 (m, 2H), 8.30 (s, 1H), 12.60 (broad s, 1H).
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl[CH2:27][C:28]#[N:29].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CC(C)=O>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([O:11][CH2:27][C:28]#[N:29])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: N#CCCl
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCSc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.3 g), chloroacetonitrile (1.4 g), triethylamine (0.61 g), and dry acetone (20 ml) is refluxed for 20 hours. After cooling the triethylamine hydrochloride formed is removed by filtration, and the filtrate is evaporated in vacuo. To the residue, water (35 ml) and ethylacetate (75 ml) are added, and the pH of the aqueous layer is adjusted to pH 7.5 by addition of 4 N hydrochloric acid. The organic layer is then separated, washed with diluted sodium hydrogen carbonate, dried and evaporated in vacuo. The residue is crystallized from chloroform petroleum ether to yield cyanomethyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate with a melting point of 134°-135° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10]I)([CH3:4])([CH3:3])[CH3:2].[I-].[CH2:14]([O:21][C:22]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:23]=1[N:29]1[S:33](=[O:35])(=[O:34])[N:32]([CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:31](=[O:42])[CH2:30]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O.[Zn]>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][C:26]1[CH:25]=[CH:24][C:23]([N:29]2[CH2:30][C:31](=[O:42])[N:32]([CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[S:33]2(=[O:35])=[O:34])=[C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)NCCCI
Agent: [I-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Zinc dust (3.6 g, 55 mmol) is placed in a flask and heated under vacuum to remove traces of water. DMF (30 mL) is then added under nitrogen atmosphere. Dibromoethane (cat. 0.5 mL) is added and the mixture heated until effervescence occurs. The reaction is allowed to cool to RT over 30 min and chlorotrimethylsilane (cat 0.5 mL) is added, followed after 30 min with (3-iodopropyl)-carbamic acid tert-butyl ester (4.0 g, 14 mmol) dissolved in 10 mL of DMF. After 30 min, TLC indicates the iodide has been consumed and Pd2(dba)3 (0.6 g) and tri-o-tolylphosphine (0.5 g) are added, followed by the dropwise addition of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (5 g, 9.2 mmol) dissolved in 25 mL of DMF. The reaction mixture is stirred for 14 h and then diluted with EtOAc and filtered through Celite. The filtrate is washed with 1M HCl, brine and water, dried over MgSO4, filtered through a short plug of silica and concentrated to afford the title compound as a light yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[C:9]=1[NH:10][C:11](=[O:14])[CH2:12][CH3:13])#[N:4].[CH2:27](I)[CH2:28][CH3:29]>O1CCCC1>[C:3]([C:5]1[CH:6]=[N:7][N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][C:16]=2[Cl:26])[C:9]=1[N:10]([CH2:27][CH2:28][CH3:29])[C:11](=[O:14])[CH2:12][CH3:13])#[N:4]
Reactant: CCCI
Reactant: CCC(=O)Nc1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCN(C(=O)CC)c1c(C#N)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Reaction time: 48 h
Yield: 66.5 %

Procedure:
0.8 g (0.033 mole) of sodium hydride is added to 10.8 g (0.03 mole) of 4-cyano-5-propionylamino-1-(2-chloro-4-trifluoromethoxyphenyl)-pyrazole in 100 ml of tetrahydrofuran and, when the evolution of gas has ended, 10.2 g (0.06 mole) of n-propyl iodide are added and the mixture is stirred at the reflux temperature for 48 hours. For working up, the mixture is concentrated in vacuo, the residue is taken up in 200 ml of methylene chloride and the mixture is washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated in vacuo. The oil which remains is purified by column chromatography (eluant: chloroform/acetone 9:1) and crystallised from petroleum ether. 8.0 g (66.6% of theory) of 4-cyano-1-(2-chloro-4-trifluoromethoxyphenyl)-5-(N-n-propyl-N-propionylamino)-pyrazole of melting point 83° C. are obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][C@@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]1=[O:1])[CH2:23]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC[C@@H](c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (4.43 g, 18.99 mmol; Example 91D) and 5-fluoroisoindoline hydrochloride (3.63 g, 20.89 mmol) in dichloromethane (30 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (5.04 mL, 28.5 mmol). After a few minutes, a dark brown solution resulted. The reaction was stirred overnight then poured into 1 N HCl (100 mL). The product was extracted into dichloromethane (3×100 mL). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in minimal dichloromethane and was loaded onto a GraceResolv™ 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes to provide the racemic title compound. Supercritical fluid chromatography using a ChiralPak® OD-H 21×250 mm column eluting using 10% to 50% methanol/CO2 over 20 minutes gave the title compound as the first eluting enantiomer. 1H NMR (300 MHz, CDCl3) δ 7.40-7.11 (m, 6H), 6.97 (dd, J=8.6, 18.0, 2H), 4.84 (dd, J=8.7, 19.3, 4H), 4.44 (dd, J=1.6, 15.7, 1H), 4.05 (d, J=15.7, 1H), 3.81-3.47 (m, 3H), 2.34-1.83 (m, 4H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[N:11]1[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[CH:32][CH:31]=2)[N:27]=[C:26]([N:39]2[CH2:45][CH:44]3[O:46][CH:41]([CH2:42][CH2:43]3)[CH2:40]2)[N:25]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1>[CH:41]12[O:46][CH:44]([CH2:43][CH2:42]1)[CH2:45][N:39]([C:26]1[N:25]=[C:24]([N:11]3[C@@H:12]([CH2:15][O:16][Si:17]([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH2:14][C@H:10]3[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[N:29]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=3)[N:27]=1)[CH2:40]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc([N+](=O)[O-])cc2)nc(N2CC3CCC(C2)O3)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@@H](CO[Si](C)(C)C(C)(C)C)N1c1nc(-c2ccc(N)cc2)nc(N2CC3CCC(C2)O3)n1

Procedure:
A suspension of palladium on charcoal (10%, 100 mg) and crude 3-(4-((2S,5R)-2,5-bis((tert-butyldimethylsilyloxy)methyl)pyrrolidin-1-yl)-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (3.4 mmol maximum) in tetrahydrofuran (30 mL) was shaken for 8 hours under 50 psi of hydrogen. The mixture was filtered through a pad of Celite™ diatomaceous earth and concentrated under reduced pressure to provide the title compound as an orange foam. MS (ES+)=642.4 (M+H)+
Reaction SMILES: B.C(SCCC(C)C)CC(C)C.B.COCCS[CH2:19][CH2:20][O:21]C.[CH3:23][C:24]1([CH3:32])[C@H:30]2[CH2:31][C@@H:25]1[CH2:26][CH2:27]C2=C.OO.[OH-].[Na+]>>[CH3:23][C:24]1([CH3:32])[C@H:30]2[CH2:31][C@@H:25]1[CH2:26][CH2:27][C@H:19]2[CH2:20][OH:21]
Reactant: COCCSCCOC
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: B
Agent: CC(C)CCSCCC(C)C
Agent: OO
Product: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Yield: 82 %

Procedure:
Hydroborations on a preparative scale were carried out with borane-diisoamyl sulfide and borane-bis(2-methoxyethyl) sulfide for illustrative purposes. Thus (-)-β-pinene (93% ee) was reacted with borane-diisoamyl sulfide and the organoborane intermediate was oxidized with standard 30% hydrogen peroxide and 3M sodium hydroxide used in excess to suppress oxidation of the sulfide. (-)-cis-Myrtanol was isolated by distillation in 82% yield and the sulfide was recovered.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)C.O.O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1ccc(C)nc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C)nc1-c1cccc(Cl)c1
Temperature: 180 °C

Procedure:
To 2-bromo-3-methoxy-6-methylpyridine (0.2 g, 1.0 mmol), 3-chlorophenylboronic acid (1) (0.19 g, 1.2 mmol), PPh3 (0.13 g, 0.5 mmol), K2CO3 (0.06 g, 0.4 mmol) and Pd(OAc)2 (0.03 g, 0.12 mmol) was added dioxane (3 mL), and EtOH—H2O (1:1, 1.5 mL). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was stirred at 180° C. for 15 m using microwave oven (Biotage Intiator II). The reaction was cooled to room temperature, concentrated, and H2O and dichloromethane (40 mL each) were added. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 1:1 dichloromethane-hexanes then dichloromethane to afford 0.19 g (81%) of I-243 as a viscous liquid.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH:10]=[O:11])=O)=[C:4]([Cl:14])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[O:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:14])[CH:3]=1
Reactant: O=CCNC(=O)c1ccc(Br)cc1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc(Br)ccc1-c1ncco1
Reaction time: 24 h
Yield: 19.8 %

Procedure:
To a stirred solution of 4-bromo-2-chloro-N-(2-oxoethyl)benzamide (1.00 g, 3.617 mmol) in CH2Cl2 (30 mL) were added triphenylphosphine (1.90 g, 7.234 mmol), iodine (1.84 g, 7.234 mmol) and triethylamine (2.0 mL, 14.47 mmol) at room temperature. After 24 hour, the mixture was washed with water (20 mL), dried over MgSO4. Removal of the solvent, gave an oily recidue, which was purified by flash chromatography eluting with ethyl acetate/hexane (1/5) to give title compound (0.185 g, 20% yield).
Reaction SMILES: C(O)C.[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11](Cl)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5].C(N(CC)CC)C.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[CH:27][CH:26]=1>CO.C(OCC)(=O)C>[C:4]([N:8]1[C:13](=[O:14])[C:12]([C:15]#[N:16])=[C:11]([NH:32][CH2:31][C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH:10]=[N:9]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)n1ncc(Cl)c(C#N)c1=O
Reactant: NCc1ccncc1
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)n1ncc(NCc2ccncc2)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Into a 30 ml of ethanol solution of 2.1 g of 2-tert-butyl-5-chloro-4-cyanopyridazin-3-(2H)-one and 1.0 g of triethylamine, 1.1 g of 4-picolylamine was dropwise added under cooling with ice over a period of 5 minutes. Then, the mixture was stirred at room temperature for two hours and then concentrated. The mixture was extracted with ethyl acetate, and the extract was washed twice with a saturated sodium chloride aqueous solution and then dried. Ethyl acetate was distilled off under reduced pressure, and the residue thereby obtained was subjected to column chromatography. Using an eluent (ethyl acetate:methanol=20:1), 2.5 g of the desired product (Compound No. 21) having a melting point of from 174 to 175° C., was obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[C:5]([CH2:7]O)[N:6]=1.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][C:4]=1[C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(-c2sc(C)nc2CO)c1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(-c2sc(C)nc2CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.3 %

Procedure:
To a stirred solution of (2-methyl-5-m-tolylthiazol-4-yl)methanol (300 mg, 1.37 mmol) in chloroform (10 mL), thionyl chloride (162 mg, 1.37 mmol) was added dropwise at rt and stirred for 30 min and then refluxed for 1 h. The reaction mixture was cooled to rt and absorbed directly on silicagel (10 g). Subsequent flash column chromatography (eluent: 7% ethyl acetate in hexane) yielded the title compound (40 mg, 12%). [LCMS RtF=1.70 min, [M+H]+=238.0; TLC Rf=0.54 (methanol/chloroform 10:90)].
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:20][C:21]([N:23]3[C@H:28]([C:29](=[O:40])[NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=4[F:39])[CH2:27][C@@H:26]4[C@H:24]3[CH2:25]4)=[O:22])=[CH:13][N:14]2[C:17](=[O:19])[NH2:18])=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:17]([N:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([CH2:7][C:6]([OH:41])=[O:5])[CH:16]=2)[C:12]([NH:20][C:21]([N:23]2[C@H:28]([C:29](=[O:40])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=3[F:39])[CH2:27][C@@H:26]3[C@H:24]2[CH2:25]3)=[O:22])=[CH:13]1)(=[O:19])[NH2:18]
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(NC(=O)N3[C@@H]4C[C@@H]4C[C@H]3C(=O)NCc3cccc(Cl)c3F)cn(C(N)=O)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)n1cc(NC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
to a solution of (1-carbamoyl-3-{[(1R,3S,5R)-3-(3-chloro-2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carbonyl]-amino}-1H-indol-6-yl)-acetic acid tert-butyl ester Example 127 (30 mg, 0.051 mmol) in CH2Cl2 (0.5 mL) was added TFA (157 μL, 2.05 mmol) and the mixture was stirred at RT for 1 h. Then concentrated and the crude residue was taken up in Et2O and filtered-off to give the desired material. MS (UPLC): 528.2/530.3 [M+H]+, 1055.6/1057.2 [2M+H]+, 483.1/485.1 [M−CONH2]−, 1053.6/1055.6 [2M−H]−; tR (HPLC conditions f): 1.75 min.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH3:11].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[CH3:11][C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: Cc1c(C(F)(F)F)noc1N
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1cccc2ccccc12
Yield: 85 %

Procedure:
N-(4-Methyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonamide was prepared, as described in Example 90, from 5-amino-4-methyl-3-trifluoromethylisoxazole and 1-naphthalenesulfonyl chloride in 85% yield. Purification was achieved by recrystallization from methanol/water to give white needed, m.p. 154°-155° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:23])[C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])C>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]([CH3:23])[C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:12]=[CH:11][C:10]=1[NH:22][CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(CN2CCOCC2)cc1N(C)Cc1ccccc1)C(=O)OCC
Temperature: 120 °C

Procedure:
A mixture of N2-benzyl-N2-methyl-4-(4-morpholinylmethyl)-1,2-benzenediamine (3.1 g, 10 mmol) and diethyl ethoxymethylenemalonate (4.2 g, 20 mmol) is heated at 120° C. until HPLC shows that the reaction is complete (20 min). The product is applied in 10% ethyl acetate/hexane to a silica gel column which is eluted with 20% ethyl acetate/hexane to remove excess diethyl ethoxymethylenemalonate and then with 50% ethyl acetate/hexane to elute 3.7 g of the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:28](O)=[O:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.B.CO>O1CCCC1.Cl.O1CCOCC1>[CH:1]1([CH2:6][CH2:7][NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:19]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(NCCC2CCCC2)cc1)N1Cc2ccc(CO)cc2C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirring suspension of 2-(4-(2-cyclopentylacetamido)phenylcarbamoyl)isoindoline-5-carboxylic acid (18 mg, 0.044 mmol) in tetrahydrofuran was added 1M borane in tetrahydrofuran (0.18 mL, 0.18 mml) dropwise. The mixture was heated at 60° C. for 1 hour. The reaction was cooled to room temperature and treated with several drops of 4M HCl-dioxane and methanol and then the clear solution was stirred at room temperature for 2 hours. The reaction was concentrated and purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.92 (s, 1H), 7.27-7.31 (m, 2H), 7.24 (d, J=8.1 Hz, 1H), 7.15-7.20 (m, 2H), 6.45-6.51 (m, 2H), 5.17-5.21 (m, 2H), 4.68-4.69 (bs, 4H), 4.51 (d, J=5.4 Hz, 2H), 2.97 (q, J=6.7 Hz, 2H), 1.70-1.95 (m, 3H), 1.42-1.66 (m, 6H), 1.04-1.20 (m, 2H); MS (ESI(+)) m/e 380 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]=1[C:14]([OH:16])=[O:15])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.C(OC(=O)C)(=O)C>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]2[C:8]([O:16][C:14](=[O:15])[C:6]=12)=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(C(=O)O)c1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOc1cccc2c1C(=O)OC2=O

Procedure:
A mixture of 45.8 g of 3-allyloxy-phthalic acid in 200 ml of toluene and 25.5 ml of acetic anhydride is heated to the reflux temperature for 3 hours and then evaporated under reduced pressure. The residue is crystallised from diethyl ether and gives 3-allyloxy-phthalic anhydride; melting point 115°-117°.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=O)OCC)C.CC([O-])(C)C.[K+].[C:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[CH:41]([CH3:43])[CH3:42]>C1COCC1>[CH3:42][CH:41]([CH3:43])[C:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[CH:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=1
Reactant: CC(C)C(=O)c1ccccc1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (921 mg; CAS 473659-21-1) at r.t. in THF (20 ml) under an argon atmosphere was added potassium tert-butylate (241 mg). The mixture was then stirred at r.t. for 15 minutes, and isobutyrophenone (0.25 ml) was added in one portion. The mixture (clear brown orange solution) was heated to 80° C. for 21 hours. The reaction mixture was filtered and the cake was washed with EtOAc. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (91 mg; not completely pure) as orange sticky solid. MS (ISP): 243.2 ([Trt]+)