Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C(Cl)(=O)C([Cl:13])=O>ClCCl>[Cl:13][CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(=O)NCO
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A flask is charged with N-hydroxymethyl-2,2-dimethyl-propionamide (0.500 g, 3.81 mmol) and dichloromethane (4 mL). Oxalyl chloride (0.8 mL, 9.52 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. Concentration in vacuo gives N-chloromethyl-2,2-dimethyl-propionamide as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (s, 9H), 5.31 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][O:8][CH:9]=[CH2:10])[CH2:6][O:5][CH2:4]1)[CH3:2].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.B1C2CCCC1CCC2.[C:40]1([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:51]=[C:50]([C:52]3[CH:53]=[C:54]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:55]=[CH:56][CH:57]=3)[N:49]=[C:48]([C:64]3[CH:69]=[CH:68][CH:67]=[C:66](Br)[CH:65]=3)[N:47]=2)[CH:41]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:40]1([C:71]2[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=2)[CH:45]=[CH:44][CH:43]=[C:42]([C:46]2[N:51]=[C:50]([C:52]3[CH:53]=[C:54]([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[CH:55]=[CH:56][CH:57]=3)[N:49]=[C:48]([C:64]3[CH:65]=[CH:66][CH:67]=[C:68]([CH2:10][CH2:9][O:8][CH2:7][C:3]4([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]4)[CH:69]=3)[N:47]=2)[CH:41]=1
Reactant: C=COCC1(CC)COC1
Reactant: Brc1cccc(-c2nc(-c3cccc(-c4ccccc4)c3)nc(-c3cccc(-c4ccccc4)c3)n2)c1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC1(COCCc2cccc(-c3nc(-c4cccc(-c5ccccc5)c4)nc(-c4cccc(-c5ccccc5)c4)n3)c2)COC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.7 %

Procedure:
13.1 g (92 mmol) of 3-ethyl-3-vinyloxymethyloxetane and 11.3 g (60.8 mmol) of 9-BBN dimer are dissolved in 200 ml of toluene at room temperature under protective gas and stirred for 20 h. During the reaction, the suspension of 9-BBN slowly dissolves. 50 g (92 mmol) of 2,4-bis-biphenyl-3-yl-6-(3-bromophenyl)-1,3,5-triazine and 50 ml of a 1 M NaOH solution are subsequently added to the reaction solution. The reaction mixture is carefully degassed, 200 mg of tetrakistriphenylphosphino-palladium are added, and the mixture is heated under reflux for 20 h. The solution is cooled to room temperature, and the phases are separated. The aqueous phase is extracted three times with toluene, the combined organic phases are subsequently washed twice with water, dried over magnesium sulfate, filtered, and the solvent is stripped off in vacuo. The residue is recrystallised from ethanol/toluene 3:1, giving 54 g (89 mmol) (97%) of a white solid in a purity of 99:8%.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21]>O1CCCC1>[CH:1]1([O:7][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:20]([F:21])([F:23])[F:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(OC2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
A solution of cyclohexanol (1.00 g, 10.0 mmol) in anhydrous tetrahydrofuran (6 ml) was added dropwise to a suspension of 60% sodium hydride (0.240 g, 6.00 mmol) in anhydrous tetrahydrofuran (6 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. 1-Fluoro-4-nitro-2-(trifluoromethyl)benzene (1.05 g, 5.00 mmol) was added to the reaction mixture under ice cooling, and the mixture was refluxed for 3 hours. Ice water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Methanol (10 ml) and 10% platinum on activated carbon (0.100 g) were added to the residue obtained by evaporation of the solvent under reduced pressure, and the mixture was stirred at room temperature for 12 hours under hydrogen atmosphere. The reaction mixture was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.60 g, 47%) as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]([OH:12])[C:9]([CH3:11])=[CH2:10])[CH:7]=1.C1COCC1.CC([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]([OH:12])[CH:9]([CH3:10])[CH3:11])[CH:7]=1
Reactant: C=C(C)C(O)c1cc(Br)ccc1F
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)c1cc(Br)ccc1F
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A flask was charged with 1-(5-bromo-2-fluorophenyl)-2-methylprop-2-en-1-ol (5.39 g, 22 mmol), THF (120 mL), and water (120 mL). With vigorous stirring, p-toluenesulfonylhydrazide (20.5 g, 110 mmol) and NaOAc (18.05 g, 220 mmol) were added successively. The mixture was then refluxed at 70° C. for 20 hours. After cooling to room temperature, saturated K2CO3 solution was added, and the mixture stirred for 5 minutes. The aqueous layer was then extracted with Et2O, dried over MgSO4, and purified by column chromatography (gradient 0 to 15% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J=6.3, 2.6 Hz, 1H), 7.34 (ddd, J=8.5, 4.5, 2.6 Hz, 1H), 6.94-6.86 (m, 1H), 4.71 (d, J=6.6 Hz, 1H), 1.97 (dq, J=13.5, 6.7 Hz, 1H), 1.84 (br s, 1H), 0.98 (d, J=6.7 Hz, 3H), 0.88 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])O.[Na+].[C:19](Cl)(=[O:21])[CH3:20].O>O1CCCC1>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][C:19](=[O:21])[CH3:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1N
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-chloro-2-methoxy-5-nitroaniline (0.3 g) and sodium hydrogen carbonate (0.37 g) in tetrahydrofuran (4.5 mL) was added acetyl chloride (0.12 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/7) to give N-(4-chloro-2-methoxy-5-nitrophenyl)acetamide (0.24 g). This material was dissolved in N,N-dimethylformamide (5 mL). To the solution were added 2,3-difluoro-6-methoxybenzyl bromide (0.28 g) and sodium hydride (55%, 48 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). To the solution were added methanol (4 mL) and nickel(II) bromide (11 mg). To the mixture was added sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/7) to give the title compound (0.27 g).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC.[C:26]1([CH3:61])[C:27]([S:32]([N:35]2[CH2:45][C:44]3=[CH:46][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:43]3[CH:47](OC(=S)OC2C=CC=CC=2)[CH2:48][CH2:49][CH3:50])(=[O:34])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1>C1(C)C=CC=CC=1>[CH2:47]([CH:43]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH:36]2[CH:46]=[C:44]1[CH2:45][N:35]2[S:32]([C:27]1[C:26]([CH3:61])=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:34])[CH2:48][CH2:49][CH3:50]
Reactant: CCCC(OC(=S)Oc1ccccc1)C1CCCCCCC2C=C1CN2S(=O)(=O)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCCC1CCCCCCC2C=C1CN2S(=O)(=O)c1ccccc1C
Temperature: 75 °C

Procedure:
AIBN (0.20 mmol) and tri-n-butyltinhydride (2.0 mmol) are added to a solution of the product of Example 7 (1 mmol) in toluene (10 mL). The mixture is stirred at 75° C. until reaction is complete as detected by thin-layer chromatography. Solvent is removed under reduced pressure and the residue is purified using high-performance liquid chromatography, affording the above-titled compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:22])([F:21])[C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][OH:20])[CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[F:11][C:12]([F:21])([F:22])[C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]=[O:20])[CH2:17][CH2:18]1
Reactant: OC[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (6.2 mL, 87.4 mmol) in anhydrous CH2Cl2 (300 mL) was added dropwise DMSO (12.5 mL, 0.17 mol) at −78° C. under N2. After the mixture was stirred at −78° C. for 30 min., a solution of (trans-4-(trifluoromethyl)cyclohexyl)methanol (5.3 g, 29.1 mmol) in CH2Cl2 (40 mL) was added dropwise while keeping the internal temperature below −65° C. After being stirred for 30 min., a solution of Et3N (40.5 mL, 0.29 mol) in CH2Cl2 (60 mL) was added dropwise slowly, keeping the internal temperature below −65° C. The reaction mixture was stirred at −78° C. for 1 h, and warmed to rt overnight. The mixture was washed with water (3×300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (eluting with 15% EtOAc in petroleum ether) to give trans-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (4.6 g, 87%) as a yellow oil.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](Cl)=[O:27])[CH:20]=[CH:19]2>C1COCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[O:27])[CH:20]=[CH:19]2
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)NC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc2cc(Br)ccc2c1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution (800 mL) of diisopropylamine (112 mL) and triethylamine (112 mL) in THF was added dropwise a solution (400 mL) of 6-bromo-2-naphthoyl chloride in THF under ice-cooling. The mixture was stirred at room temperature for 1 hr. A half amount of the solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed successively with water, 1N aqueous sodium hydroxide solution, water and saturated brine and dried over magnesium sulfate. The solvent was evaporated and the obtained solid was washed with isopropyl ether to give the title compound (117 g) as colorless flakes.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][O:6][C@H:5]([C@@H:8]([OH:22])[CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH:33]=O)[N:24]=1>>[N:23]1[C:28]2[O:29][CH2:30][CH2:31][O:32][C:27]=2[CH:26]=[C:25]([CH2:33][NH:1][C@H:2]2[CH2:7][O:6][C@H:5]([C@@H:8]([OH:22])[CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=4)[N:13]=[CH:12][CH:11]=3)[CH2:4][CH2:3]2)[N:24]=1
Reactant: COc1ccc2nccc(C[C@H](O)[C@@H]3CC[C@@H](N)CO3)c2n1
Reactant: O=Cc1cc2c(nn1)OCCO2
Product: COc1ccc2nccc(C[C@H](O)[C@@H]3CC[C@@H](NCc4cc5c(nn4)OCCO5)CO3)c2n1

Procedure:
Starting from (1S)-1-((2S,5R)-5-amino-tetrahydro-pyran-2-yl)-2-(6-methoxy-[1,5]naphthyridin-4-yl)-ethanol (0.1 g, 0.33 mmol, prepared according to WO 2006/032466) and 6,7-dihydro-[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (0.06 g, 1 eq.; prepared according to WO 2007/071936), and using the procedure of Example 1, the title compound was obtained as a colourless oil (0.008 g, 8% yield). The compound was purified by CC (DCM-MeOH 93-7 containing 0.7% aq. NH4OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Br[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[N:21]3[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[N:25][C:20]3=[N:19][CH:18]=2)=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: OB(O)c1ccc(F)c(-n2cncn2)c1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-n1cncn1

Procedure:
4-Fluoro-3-([1,2,4]triazol-1-yl)phenylboronic acid (100 mg, 0.48 mmol) was coupled to 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine (117 mg, 0.44 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 2% methanol, then recrystallisation from dichloromethane/isohexane, gave 3-[4-fluoro-3-([1,2,4]triazol-1-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a yellow solid: δH (360 MHz, CDCl3) 7.31 (1H, d, J 7), 7.51-7.60 (2H, m), 8.16 (2H, m), 8.21 (1H, dd, J 7 and 2), 8.80-8.83 (2H, m); m/z (ES+) 349 (M++H).
Reaction SMILES: [CH2:1]([OH:3])C.C([O-])=O.[NH4+].C(O)=O.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd].O>[C:12]1([CH:11]([OH:18])[CH2:1][OH:3])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: OCC(O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
Pd/C (5 mol %) is weighed into a reaction flask. A solvent mixture consisting of ethanol and water (4:1) and ammonium formate (30 mol %) is added, the reaction flask is capped with a rubber septa and the mixture is heated (80° C.) for 2 minutes. Formic acid (3 equivalents) and then benzyl alcohol are added by syringe. The reaction is run for 10-40 minutes and the reaction is quenched with brine. The product is extracted by DCM and the organic phase is dried by Na2SO4. The product 1-phenyl-2-propanol was analyzed by 1H NMR and produced in 60% yield.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15].Cl[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>C(#N)C.O>[C:7]1([CH3:17])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:15]
Reactant: CCOC(=O)CCl
Reactant: Cc1ccccc1CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COC(=O)Cc1ccccc1C
Temperature: 25 °C

Procedure:
Potassium carbonate (25 g) was added to a stirred solution of o-tolylacetic acid (7.5 g) in acetonitrile (125 ml). The mixture was stirred for ten minutes at room temperature. Ethyl chloroacetate (6.13 g) was added and the mixture heated at reflux overnight. It was then poured into water, acidified with concentrated hydrochloric acid to pH2 and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated, and purified by column chromatography to give ethoxycarbonylmethyl o-tolylacetate. Potassium carbonate 15 g) was added to a stirred solution of this product (10 g) in dimethylformamide (100 ml). The mixture was stirred at room temperature for 72 hours and then heated at reflux overnight. The mixture was cooled to 0° C. and potassium carbonate (5 g) added, followed by methyl iodide (2.65 ml). The mixture was stirred at room temperature for 24 hours. The mixture was poured into water, extracted with ether and the extract washed with brine, dried and evaporated to give 3-(2-methylphenyl)-4-methoxyfuran-2(5 H)-one, as a gum. This was then treated with N-bromosuccinimide followed by reaction with 2-mecaptobenzothiazole, in a similar manner to that described in Example 1, to give 3-[2-[[(2-benzothiazolyl)thio]methyl]phenyl]-4-methoxyfuran-2(5H)-one m.p. 81°-82°. (Compound 2)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CON(C)[C:18]([CH:20]1[CH2:22][CH:21]1[CH3:23])=[O:19]>CCCCCC>[CH3:9][C:4]1[CH:3]=[C:2]([C:18]([CH:20]2[CH2:22][CH:21]2[CH3:23])=[O:19])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CON(C)C(=O)C1CC1C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C)cc(C(=O)C2CC2C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-meta-xylene (5.7 mL in 120 mL of dry tetrahydrofuran) at -78° C. was added 30.6 mL of a 1.4M solution of n-butyllithium in hexane and the mixture stirred at low temperature. After 15 minutes, a solution of 2-methylcyclopropanecarboxylic acid N-methoxy-N-methyl-amide (5.0 g in 50 mL tetrahydrofuran) was added dropwise over 5 minutes and the mixture then allowed to warm slowly to room temperature. After 1 hour, the reaction was quenched by the addition of 20 mL 2N hydrochloric acid and 40 mL water. This was extracted with ethyl acetate washed with saturated sodium bicarbonate and brine then dried over sodium sulfate to give 6.95 g of the title compound (crude).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl.[C:13]([C:15]1[CH:28]=[CH:27][C:18]([CH2:19][N:20]2[C:24]([CH2:25]Cl)=[CH:23][N:22]=[CH:21]2)=[CH:17][CH:16]=1)#[N:14].O>CN(C=O)C.C(Cl)(Cl)Cl.CCOCC.CO>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[C:24]([CH2:25][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:23][N:22]=[CH:21]2)=[CH:27][CH:28]=1)#[N:14]
Reactant: c1ccc2[nH]ccc2c1
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(Cn2cncc2Cn2ccc3ccccc32)cc1
Reaction time: 16 h

Procedure:
Indole (117 mg, 1.0 mmol) dissolved in DMF (15 mL) was treated with NaH (48 mg, 2 mmol) and stirred for 30 minutes before the addition of the chloride from Step 1 (268 mg, 1 mmol). The mixture was stirred for 16 h, poured into water, extracted with EtOAc (3×), washed with aqueous NaHCO3 then brine, dried and evaporated to give an oil. Chromatography of this oil (silica gel; 2.5% MeOH in CHCl3) gave an oil which solidified when stirred in ether. Filtration afforded the title product as an off-white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([Cl:14])(=[O:13])=[O:12].Cl.Cl.[CH3:17][O:18][C:19](=[O:34])[CH:20]([NH2:33])[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([NH2:32])=[N:27][CH:26]=[CH:25]2.[OH-].[Na+].Cl>ClCCl.C(N(CC)CC)C.C(O)(C)(C)C.O.ClCCl.CO.O.O1CCOCC1>[ClH:14].[CH3:17][O:18][C:19](=[O:34])[CH:20]([NH:33][S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12])[CH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([NH2:32])=[N:27][CH:26]=[CH:25]2
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: COC(=O)C(N)Cc1ccc2c(N)nccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 35.8 %

Procedure:
0.10 g of 2-naphthalenylsulfonylchloride dissolved in 0.8 mL of dichloromethane and 0.2 mL of dioxane was added to a solution of 0.13 g of 1j in 6 mL dichloromethane and 0.17 mL of triethylamine at 0° C. After stirring at room temperature for 1 hour water was added , sodium hydroxide was added until pH 8-9 and the mixture was extracted with dichloromethane. The dichloromethane extract was dried (MgSO4) and concentrated. Purification (silica gel, dichloromethane/methanol 95/5), addition of one equivalent of hydrochloric acid and lyophilisation (t-butanol/water) gave 69 mg of 11a. 1H-NMR 200 MHz (CDCl3) δ: 3.00-3.34 (2H, m), 3.49 (3H, s), 4.34 (1H, dd, J=5 Hz and J=9 Hz), 6.72 (1H, d, J=7 Hz), 7.25-7.87 (9H, m), 8.04 (1H, d, J=8 Hz), 8.16 (1H, d, J=2 Hz).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.C(N(CC)CC)C.[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36])([O-:28])=[O:27].O>C(Cl)Cl>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([O:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1)(=[O:37])=[O:36])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COS(=O)(=O)c2ccccc2[N+](=O)[O-])OC(C)(C)O1
Reaction time: 24 h
Yield: 122.9 %

Procedure:
To a stirring 20°-25° C. solution of the (4R cis)-1,1-dimethylethyl 6-hydroxymethyl-2,2-dimethyl -1,3-dioxane-4-acetate (European Patent Application 0319,847) (10 g, 0.038 mol) in methylene chloride (250 mL) containing triethylamine (7 mL, 0.05 mol) is added 2-nitrobenzenesulfonyl chloride (9.8 g, 0.043 mol). Stirring is continued at 20°-25° C. for 24 hours, a further portion of 2-nitrobenzenesulfonyl chloride (2.0 g, 0.009 mol) is added and the solution stirred for a further 4 hours. The solution is then poured onto 200 mL of water and the layers separated. The upper aqueous layer is extracted with 250 mL of methylene chloride and the combined organic layers are washed with 100 mL each of saturated sodium bicarbonate solution to ensure complete removal of 2-nitrobenzenesulfonyl chloride and then saturated sodium chloride. Drying the solution with magnesium sulfate and concentration in vacuo gives 20.8 g of the product as a green oil.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:13])[CH3:12])[CH:7]=[N:8][C:9]=1[Cl:10]>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:13])[CH3:12])[CH:7]=[N:8][C:9]=1[Cl:10]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
To a well stirred suspension of sodium borohydride (66.21 g, 1.75 mole) in methanol (3.5 L) cooled to 0° C. with a Dry Ice/acetone bath was added 1-(5,6-dichloro-pyridin-3-yl)-ethanone 14 (665 g, 3.5 mole) at a rate such that the temperature remained at 0° C. After solid addition was complete, the reaction mixture was stirred an additional 1 h, after which time LC/MS analysis of an aliquot showed that the reaction was complete.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:30])[CH:28]=[CH2:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[C:27](=[O:30])[CH2:28][CH2:29][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: C=CC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCc4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-{4′-[4-(1-hydroxy-allyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-3-trifluoromethyl-benzene. The crude material was purified on silica gel (0-60% EtOAc in hexanes) to give a separable mixture of two compounds, one of which was the title compound.