Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH:2]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:11][CH2:10][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)O)c1
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cccc(CBr)c1
Temperature: -20 °C
Reaction time: 1.25 h
Yield: 60.5 %

Procedure:
In a 1 L round bottom flask fitted with a reflux condenser, a stirred suspension of 10.00 g of m-toluic acid and 14.37 g (1.1 eq.) N-bromosuccinimide in 735 mL chloroform was sparged for 0.5 h with nitrogen. The sparging was discontinued, and the suspension was stirred and irradiated under nitrogen atmosphere using a 500 W quartz halogen lamp at 75% power, causing the solids to dissolve and the chloroform to reflux. The red color of the reaction mixture disappeared after 1.25 h, and 14.37 g of N-bromosuccinimide was added. The reaction mixture was stirred and irradiated under nitrogen atmosphere with a 500 W quartz halogen lamp at 75% power for another 1.5 h, at which time the solution became colorless. The solvent volume was reduced in vacuo to about 100 mL, and then cooled to −20° C. The resultant suspension was vacuum filtered through a bed of dry silica. The silica was washed with 800 mL of chloroform. The chloroform filtrate was reduced in vacuo to about 100 mL, and then cooled to −20° C. The resultant crystals were vacuum filtered, washed with 30 mL of chloroform followed by 50 mL of hexanes, then dissolved in 250 mL chloroform and washed in a separatory funnel with 3×300 mL volumes of water followed by one 300 mL volume of brine to remove traces of succinimide. The organic phase was dried with magnesium sulfate, vacuum filtered, and the solvent was removed in vacuo to provide 9.56 g (61%) of 3-bromomethylbenzoic acid as a white crystalline power.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:29]=2)[C:19]([C:34]#[N:35])=[C:18]([SH:36])[N:17]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([C:24]2[CH:25]=[N:26][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:29]=2)[C:19]([C:34]#[N:35])=[C:18]([S:36][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[S:6][CH:7]=2)[N:17]=1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc(OCCO)nc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)nc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
63 mg (0.26 mmol) of 4-chloromethyl-2-(4-chlorphenyl)thiazole, 100 mg (0.23 mmol) of the compound from example 2A and 78 mg (0.93 mmol) of sodium bicarbonate are dissolved in 1.5 ml of DMF, and the reaction solution is stirred at RT for 20 h. The mixture is then filtered through a paper filter, and the filtrate is directly purified chromatographically by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). This gives the title compound as a beige solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:10]=1.FC1C(F)=CC=CC=1CSC1N=C(NS(N2CCC2)(=O)=O)C=C(OC(CO)CO)N=1.[H-].[Na+]>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:12]=[C:13]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:14]=1
Reactant: CC(O)CN(C)C
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: O=S(=O)(Nc1cc(OC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in Example 41 step i) using 1-dimethylamino-2-propanol (80 mg), 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1 step (0.25 g) and 60% sodium hydride (30 mg) in THF (2 mL) at room temperature for 2 d to give the subtitle compound as a pale yellow gum. Yield: 0.29 g.
Reaction SMILES: C[Al](C)C.[CH2:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][C:16]([C:19]([O:21]C)=O)=[CH:15][N:14]=2)[CH2:9][CH:8]1[CH3:23])[CH3:6].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:19]([C:16]3[CH:17]=[N:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH2:5][CH3:6])[CH:8]([CH3:23])[CH2:9]4)=[N:14][CH:15]=3)=[O:21])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCN1CCN(c2ncc(C(=O)OC)cn2)CC1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCN1CCN(c2ncc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)CC1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Trimethylaluminium (2M in toluene, 1.65 ml, 3.31 mmol) was added dropwise to a stirred suspension of methyl 2-(4-ethyl-3-methylpiperazin-1-yl)pyrimidine-5-carboxylate (303 mg, 1.15 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (283 mg, 1.15 mmol) in toluene (5.73 ml) at room temperature. The resulting solution was stirred at 60° C. overnight. The reaction mixture was quenched into methanol (100 mL) and treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product as a yellow dry film. The crude product was purified by preparative HPLC, 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 title compound (269 mg, 49%) as a cream solid.
Reaction SMILES: [CH3:1][C@@:2]12[C@:10]([OH:18])([CH2:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:19][CH2:20][C:21]3[C:26]([F:27])=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=3[C@H:5]1[CH2:4][CH2:3]2.ClC1C=C(C=CC=1)C(OO)=[O:35]>ClCCl>[CH3:1][C@@:2]12[C@:10]([OH:18])([CH2:11][C:12]3[CH:13]=[CH:14][N+:15]([O-:35])=[CH:16][CH:17]=3)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:19][CH2:20][C:21]3[C:26]([F:27])=[C:25]([C:28]#[N:29])[CH:24]=[CH:23][C:22]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC[C@@H]3c4ccc(C#N)c(F)c4CC[C@H]3[C@@H]1CC[C@@]2(O)Cc1ccncc1
Solvent: ClCCl
Product: C[C@]12CC[C@@H]3c4ccc(C#N)c(F)c4CC[C@H]3[C@@H]1CC[C@@]2(O)Cc1cc[n+]([O-])cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 74.9 %

Procedure:
To a solution of EM-5855 (86 mg, 0.22 mmol) in anhydrous dichloromethane (5 mL) at 0° C. was added 3-chloroperoxybenzoic acid (54 mg, 0.22 mmol). The mixture was stirred for 16 h at 22° C. and evaporated to dryness. The crude compound was purified by flash chromatography (silica gel, 0-10% methanol in chloroform) to give 67 mg (75%) of EM-5854. 1H NMR (400 MHz, CDCl3) δ: 0.94 (s, 3H, Me), 2.57 (d, Jgem=13.5 Hz, 1H, —CH2-Pyr), 2.68 (m, 1H, H-6), 2.93 (d, Jgem=13.3 Hz, 2H, —CH2-Pyr, H-6), 7.17 (d, J=8.3 Hz, 1H, Ar), 7.27 (d, J=6.0 Hz, 2H, Pyr), 7.36 (t, J=7.7 Hz., 1H, Ar), 8.01 (d, J=6.8 Hz, 2H, Pyr).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][C:29]2[N:33]([CH3:34])[N:32]=[N:31][N:30]=2)[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][C:29]2[N:33]([CH3:34])[N:32]=[N:31][N:30]=2)[CH2:10]1
Reactant: Cn1nnnc1SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Product: Cn1nnnc1SC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.67 g) in methanol (30 ml) was added conc. hydrochloric acid (0.82 ml) at ambient temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (80 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.25 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].C(Cl)Cl.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(O)(=O)C1C=CC=CC=1>C(N(CC)CC)C.O1CCCC1>[C:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)O)cc1C(C)=O

Procedure:
To a suspension of 2.3 g. of 4-hydroxy-3-acetylbenzoic acid in 100 ml. of methylene chloride and 100 ml. of tetrahydrofuran, a mixture of 1.5 g. of triethylamine, 1.6 g. of 4-N-dimethylaminopyridine and 1.5 g. of acetic anhydride is added. The reaction mixture is heated at 50° for one hour. The solution is extracted with ethyl acetate, the organic layer washed with water and dilute hydrochloric acid and evaporated to dryness to yield 2.1 g. of the benzoic acid product. NMR in CDCl3
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH:29]=[CH:28]1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:27](/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31])=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C(O)/C=C\C(=O)NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
A mixture of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (420 mg, 1.2 mmol) and maleic anhydride (118 mg, 1.2 mmol) was stirred for 30 minutes in xylene at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, which was recrystallized from chloroform-ethanol-diethyl ether to give 420 mg (yield 78%) of the titled compound, m.p. 207°-209° C.
Reaction SMILES: C(O)(C)C.[CH2:5]([NH2:15])[C:6]1[CH:14]=[CH:13][C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=1.[Cl:16][C:17]1[N:26]=[C:25](Cl)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:28]#[N:29])[CH:23]=2)[N:18]=1>C(N(CC)CC)C>[Cl:16][C:17]1[N:26]=[C:25]([NH:15][CH2:5][C:6]2[CH:14]=[CH:13][C:12]3[O:11][CH2:10][O:9][C:8]=3[CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:28]#[N:29])[CH:23]=2)[N:18]=1
Reactant: N#Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 79.4 %

Procedure:
35 ml of isopropyl alcohol, 900 mg of triethylamine and 1.35 g of piperonylamine were added to 2 g of 2,4-dichloro-6-cyanoquinazoline. The obtained mixture was heated under reflux for 1.5 hours and hot-filtered to recover a precipitate. Thus, 2.4 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[CH3:17])[N:5]=[C:4]([O:18][CH2:19][CH2:20][OH:21])[N:3]=1.Br[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:18][CH2:19][CH2:20][O:21][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[N:5]=[C:6]([NH:9][CH2:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[CH3:17])[C:7]=1[CH3:8]
Reactant: Cc1nc(C)c(CNc2nc(OCCO)nc(Cl)c2C)s1
Reactant: Brc1ccc2cccnc2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(C)c(CNc2nc(OCCOc3ccc4cccnc4n3)nc(Cl)c2C)s1
Reaction time: 8 h

Procedure:
2-[(4-chloro-6-{[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amino}-5-methylpyrimidin-2-yl)oxy]ethanol G1 (17 mg, 0.052 mmol) and 2-bromo-1,8-naphthyridine (11 mg, 0.053 mmol) were placed in a test tube and dissolved in THF (1 mL). A 2 M solution of NaHMDS in THF (39 μL, 0.078 mmol) was added at ambient temperature, and the reaction was stirred overnight. Solvent was then removed, and the product was purified by silica gel flash column chromatography (EtOAc/hexanes gradient). 10 mg (42%) of G2 were isolated as an off-white solid. 1H NMR (499 MHz, DMSO-d6): δ 8.97 (s, 1H); 8.56 (d, J=8.03 Hz, 1H); 8.44 (d, J=8.81 Hz, 1H); 7.89-7.84 (m, 1H); 7.62 (dd, J=7.95, 4.62 Hz, 1H); 7.26 (d, J=8.79 Hz, 1H); 4.78 (d, J=5.18 Hz, 2H); 4.66 (d, J=4.97 Hz, 2H); 4.57 (d, J=5.78 Hz, 2H); 2.47 (s, 3H); 2.30 (s, 3H); 2.01 (s, 3H). HRMS (Electrospray): m/z 457.1206 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].[C:24]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1>C1COCC1>[C:24]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:15]2[C:14](=[O:17])[CH2:13][CH2:12][C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:16]2)=[CH:35][CH:34]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1
Reactant: O=C(Nc1ccc(CCl)cc1)c1cccnc1
Reactant: COc1ccc(C2=NNC(=O)CC2)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=NN(Cc3ccc(NC(=O)c4cccnc4)cc3)C(=O)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
A suspension of 4.70 g of 6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one ("A") in 150 ml of THF is treated with 2.24 g of potassium tert-butoxide and the mixture is stirred for 30 minutes. 7.32 g of 4-nicotinoylaminobenzyl chloride is added and the mixture is subsequently stirred at room temperature for 10 hours. The solvent is removed and the residue is worked up in the customary manner. 2-(4-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one is obtained.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C-:18]#[N:19].[Na+].CS(C)=O>O>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][C:18]#[N:19])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc(CC#N)cc2)CC1
Temperature: 140 °C

Procedure:
114 g (0.45 mol) of 4-(trans-4'-propylcyclohexyl) benzyl chloride, 27 g (0.55 mol) of NaCN and 113 cm3 of DMSO were mixed and while stirring, the mixture was heated to a temperature of 140° C. by a mantle heater. The product of the reaction was cooled to room temperature. 400 cm3 of water was added and extracted three times with 100 cm3 of chloroform. The chloroform layers were combined and washed with 10% hydrochloric acid and water. The chloroform was distilled off under reduced pressure and the residue was distilled under reduced pressure (155° C./2.5 mmHg) to yield 106 g (0.44 mol) of 4-(trans-4'-propylcyclohexyl) benzyl cyanide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=2[CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (2.96 g), 2-isopropyl-4-nitrophenol (2.66 g) and triphenylphosphine (5.00 g) in dichloromethane (80 ml) was added diethyl azodicarboxylate (3.0 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane as an eluant to give the desired compound (4.07 g, yield 76%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].C(N(CC)CC)C.[CH2:18]([O:20][C:21]([C:23]1[S:24][C:25]([C:28](Cl)=[O:29])=[CH:26][CH:27]=1)=[O:22])[CH3:19]>C(#N)C>[CH2:18]([O:20][C:21]([C:23]1[S:24][C:25]([C:28](=[O:29])[NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:26][CH:27]=1)=[O:22])[CH3:19]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1ccc(C(=O)Cl)s1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 22 h
Yield: 90 %

Procedure:
Starting material (12(e)) was prepared as follows. To a stirring solution of 3,4-dichlorobenzylamine (0.53 mL; 4.0 mmole) in acetonitrile (10 mL) was added triethylamine (1.67 mL; 12.0 mmole) and a solution of (11(a)) (0.87 g; 4.0 mmole, see Example 11) in acetonitrile (20 mL). The solution was stirred at ambient temperature. under argon, for 22 hours. The solvent and excess triethylamine were removed in vacuo and the residue partitioned between chloroform and water. The organic phase was washed with water and brine, dried over magnesium sulphate and vacuumed to dryness to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carboxylic acid ethyl ester (12(a)) as a cream solid ( 90%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](Cl)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:18][NH2:19]>C(N(CC)CC)C.C(O)CO.O>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:18][NH2:19])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Cl)cc1
Reactant: NN
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O
Product: NNc1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
A mixture of 4-chlorophenyl phenyl sulfone (10.1 g, 40.0 mmol), hydrazine mono-hydrate (30 mL), and triethylamine (4 drops) in ethylene glycol (20 mL) is heated at 150° for 15 hr. Upon cooling, the mixture is diluted with H2O and filtered. The residual solid is washed with H2O until the washings are neural (pH=6). This material is then triturated with methylene chloride and dried under reduced pressure at 50° to give the title compound, IR (drift) 3282, 1586, 1514, 1306, 1291, 1158, 1145, 1104, 996, 813, 756, 730, 717, 688 and 678 cm−1; NMR (300 MHz, CDCl3) 7.70-7.85, 7.45-7.65, 6.79 and 4.22 δ; MS (EI) m/z 248 (M+), 125, 123, 108, 107, 90, 80, 77, 63 and 51.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43]([OH:54])[C@@H:44]([OH:53])[C@@H:45]([OH:52])[C@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48]O>>[OH:50][C@H:47]([C@@H:46]([OH:51])[C@H:45]([OH:52])[C@H:44]([OH:53])[CH2:43][OH:54])[CH2:48][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (2R,3R,4R,5S)-hexane-1,2,3,4,5,6-hexaol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl ester. MS (ES+) m/z calcd. for C37H42Cl2F2N3O9: [(M+H)+]: 780. found: 780.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 28 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A solution of 2-[(6-methoxy-pyridin-3-ylamino)-methylene]malonic acid diethyl ester (260.0 g, 1.365 mol, 1.0 eq) in diphenyl ether (500 mL) is heated to reflux. While the ethanol formed is removed by azeotropic distillation the reflux temperature reached 245° C. The reaction mixture is kept at 245° C. for 3 hours, then it is cooled to 28° C., a brown solid precipitated and is collected by filtration and washed with hexane (500 mL). The solid is dried under vacuum to afford 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a brown powder (74.2 g, 32% yield).