Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH2:4][C:3]1=[O:18].[OH-].[Na+]>Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)[CH2:4][C:3]1=[O:18]
Reactant: CN1CCN(C2CCC3(CC2)OCCO3)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(C2CCC(=O)CC2)CC1=O

Procedure:
2.3 g 8-(4-methyl-3-oxo-piperazin-1-yl)-1,4-dioxa-spiro[4,5]decane are stirred in 20 ml of 4M HCl for 48 hours at ambient temperature, for 7 hours at 50° C. and for two hours at 70° C. The mixture is made alkaline with 4M sodium hydroxide solution and extracted five times with 40 ml dichloromethane. The organic phase is evaporated down and the product is purified by column chromatography.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:23][O:24][C:25](=[O:73])[C@@H:26]([NH:42][C:43]([C@@H:45]1[CH2:54][C:53]2[CH:52]=[C:51]3[O:55][CH2:56][C@H:57]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH:67]5[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]5)[CH:60]=4)[O:58][C:50]3=[CH:49][C:48]=2[CH2:47][NH:46]1)=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=2[CH3:41])=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.CO>[CH3:23][O:24][C:25](=[O:73])[C@@H:26]([NH:42][C:43]([C@@H:45]1[CH2:54][C:53]2[CH:52]=[C:51]3[O:55][CH2:56][C@H:57]([C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH:67]5[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]5)[CH:60]=4)[O:58][C:50]3=[CH:49][C:48]=2[CH2:47][N:46]1[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[CH3:10])=[O:9])=[O:44])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[C:35]=2[CH3:41])=[CH:30][CH:29]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1cccc(OCC2CCCCC2)c1)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1cccc(OCC2CCCCC2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 mL of anhydrous DCM and EDCI (9 mg), HOBT (7 mg) and (S)-2-{[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0° C. and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was loaded onto a silica gel column (1:3 EtOAc/hexanes to 4% MeOH in 1:1 EtOAc/hexanes) to get pure (S)-2-{[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (22 mg). This product was hydrolyzed according to General Procedure B to the title compound (17 mg). LCMS (m/z): 800.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]>>[C:16]([O:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])(=[O:21])[CH2:17][C:18]([CH3:20])=[O:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Product: CC(=O)CC(=O)OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of 22.8 g (0.111 mol) of N-3-hydroxypropyl phthalimide and 14.46 g (0.111 mol) of ethyl acetoacetate was heated at 145°-150° C. for 12 hours. Ethanol was removed with nitrogen flow during the course of the reaction. The mixture was cooled to room temperature, dissolved in dichloromethane, and washed with brine. The separated organic phase was dried over magnesium sulfate, concentrated in vacuo, and distilled at 211°-219° C. (0.125 mm Hg) to yield 17.3 g (54%) of a white solid; m.p. 67°-71° C. NMR: (CDCl3) δ 2.0 (2H,m), 2.2 (3H,s), 3.3 (2H,s), 3.7 (2H,t), 4.05 (2M,t), 7.62 (4H,d).
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)=O.[NH2:11]/[C:12](/[CH3:19])=[CH:13]\[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH3:19][C:12]1[N:11]=[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:3]2=[CH:1][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=CC1CCCCCC1=O
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)c1cc2c(nc1C)CCCCC2
Yield: 47.8 %

Procedure:
2-Formylcycloheptanone (1.70 g, 12.1 mmol) and ethyl 3-aminocrotonate (1.58 g, 12.1 mmol) were stirred at 100° C. for 15 hours. After cooling, the reaction solution was purified by a silica gel column chromatography (ether/hexane=1:3) to obtain the title compound (1.35 g, 46.1%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([Cl:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[Cl:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)c(Cl)c2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2Cl)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (2′-chloro-4′-{4 -[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.Br[CH2:36][C:37]([O:39][CH2:40]C)=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:7]2[C:2](=[O:1])[N:3]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:34]3)[C:4]3[N:5]([N:26]=[CH:27][N:28]=3)[C:6]=2[CH2:23][CH2:24][CH3:25])=[CH:14][CH:13]=1)#[N:22]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(CC(=O)OC)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (453 mg), ethyl bromoacetate (184 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (418 mg, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][NH:15][C:16]([CH:18]3[O:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[O:17])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.I[C:25]1[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([CH2:14][NH:15][C:16]([CH:18]3[O:23][CH2:22][CH2:21][N:20]([C:25]4[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=4[C:27]([O:29][CH3:30])=[O:28])[CH2:19]3)=[O:17])=[C:11]([CH3:13])[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CNC(=O)C1CNCCO1
Reactant: COC(=O)c1ccccc1I
Product: COC(=O)c1ccccc1N1CCOC(C(=O)NCc2sc(-c3ccc(Cl)cc3)nc2C)C1
Yield: 85.6 %

Procedure:
Using N-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methyl]morpholine-2-carboxamide (54.4 mg, 0.155 mmol) and methyl 2-iodobenzoate (40.6 mg, 0.155 mmol), the same procedure was followed as in Example 58 to give 64.5 mg (86%) of the desired compound as a colorless powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([C:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:12]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reaction time: 20 h
Yield: 41.3 %

Procedure:
To a stirred solution of 23.5 g (0.35 mole) of imidazole in 425 mL of ethyl acetate was added 48.0 g (0.32 mole) of triphenylmethyl chloride. The mixture was stirred for 20 hours and then 500 mL of water was added. After being stirred for an additional 2 hours, the mixture was filtered. The ethyl acetate layer was separated, dried (MgSO4) and concentrated. Recrystallization of the residue from xylene gave 41 g of white crystals, mp 222°-225° C..
Reaction SMILES: [OH:1][N:2]=[C:3]([C:14]#[N:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1.[CH2:16]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.O>O1CCCC1>[CH2:16]([C:28]1[CH:29]=[CH:30][C:31]([S:34]([O:1][N:2]=[C:3]([C:14]#[N:15])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=2)(=[O:36])=[O:35])=[CH:32][CH:33]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(C#N)=NO)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 40.9 %

Procedure:
Analogously to the preparation of Example 1, 14.4 g (0.07 mol) of α-hydroxyimino-3,4-dimethoxybenzyl cyanide are reacted at room temperature with 26.56 g (0.077 mol) of 4-dodecylbenzenesulfonyl chloride in 100 ml of tetrahydrofuran in the presence of 10.6 g (0.105 mol) of triethylamine. For working-up, the reaction mixture is poured into water and extracted several times with methylene chloride. After drying over magnesium sulfate, the solvent is distilled off in a rotary evaporator. The brown oil that remains is then purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:1). 14.75 g (41%) of α-(4-dodecylphenylsulfonyloxyimino)-3,4-dimethoxybenzyl cyanide are obtained in the form of a viscous yellow oil. The 1H-NMR spectrum shows that it is the (syn) isomer. The UV/Vis spectrum (acetonitrile) shows an absorption band at 350 nm (ε=10700) that extends to 435 nm. Elemental analysis: C28H38N2O5S
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)C.[C:9](OCC)(=O)[C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[NH:22]1C=CN=C1>CN(C)C=O>[NH2:22][CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11]
Reactant: CCOC(=O)[C@@H](O)c1ccccc1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: NC[C@@H](O)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 31.4 g of t-butyldimethylsilyl chloride in 200 ml of dimethylformamide was added dropwise to a solution of 25 g of ethyl (S)-(+)-mandelate and 28.4 g of imidazole in 800 ml of dimethylformamide, and the resulting mixture was stirred overnight at 40° C. At the end of this time, the dimethylformamide solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give the title compound having an Rf=0.84 (thin layer chromatography over silica gel, using a 10: 1by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(NC(C)C)(C)C.Cl.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:30]#[N:31])[C:24]=2[CH2:23][CH2:22]1.[N:32]1([C:38]2[N:39]=[C:40]([CH2:45][C:46]([O-])=[O:47])[NH:41][C:42](=[O:44])[CH:43]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[Na+]>CN(C)C=O>[N:32]1([C:38]2[N:39]=[C:40]([CH2:45][C:46]([N:21]3[C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:30]#[N:31])[C:24]=4[CH2:23][CH2:22]3)=[O:47])[NH:41][C:42](=[O:44])[CH:43]=2)[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: N#Cc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.3 %

Procedure:
242 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, 371 mg of N,N-diisopropylamine and 210 mg of 2,3-dihydro-1H-indole-4-carbonitrile hydrochloride are added to a solution of 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, obtained according to example 1c, step 2c, in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 72 hours and then concentrated under reduced pressure. The residue is taken up with 100 ml of water and 20 ml of ethyl acetate, and then stirred at ambient temperature for 1 hour. The precipitate formed is filtered off, and then rinsed successively with water and petroleum ether. The solid obtained is dried with suction, and then dried under reduced pressure at 40° C. 190 mg of 1-{[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}-2,3-dihydro-1H-indole-4-carbonitrile are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:10]=[C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)[C:8]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][C:6]=1[O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[OH:4])#[CH:2].I[C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1.C(N(CC)CC)C>O.C(OCC)C>[OH:4][CH:3]([C:5]1[CH:10]=[C:9]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)[C:8]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:7][C:6]=1[O:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])[C:1]#[C:2][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(C23CC4CC(CC(C4)C2)C3)c(OCOCCOC)cc1OCOCCOC
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COCCOCOc1cc(OCOCCOC)c(C23CC4CC(CC(C4)C2)C3)cc1C(O)C#Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
760 mg (1.6 mmol) of a-ethynyl-5-(1-adamantyl)-2,4-di(methoxyethoxymethoxy)benzenemethanol, 420 mg (1.6 mmol) of methyl 4-iodobenzoate and 20 ml of triethylamine were introduced into a three-necked flask. The reaction medium was degassed with nitrogen for 30 min, then 90 mg of bis(triphenylphosphine)palladium(II) chloride and 37 mg of copper iodide were added successively. The reaction medium was stirred at room temperature for four hours, then evaporated to dryness, and the residue obtained was taken up in water and ethyl ether. The organic phase was separated out after settling had taken place, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a column of silica, eluted with dichloromethane and 800 mg (82%) of the expected methyl ester were recovered in the form of a brown oil.
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8](=[NH:10])[S:9][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](/[N:10]=[C:8]1\[S:9][C:5]2[CH:4]=[C:3]([F:2])[CH:16]=[CH:15][C:6]=2[N:7]\1[CH2:11][CH2:12][O:13][CH3:14])=[O:24]
Reactant: COCCn1c(=N)sc2cc(F)ccc21
Reactant: COc1ccc(F)cc1C(=O)O
Agent: Br
Product: COCCn1/c(=N/C(=O)c2cc(F)ccc2OC)sc2cc(F)ccc21

Procedure:
The product from Example 113A and 5-fluoro-2-methoxy-benzoic acid were processed using the methods described in Example 13 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.23 (s, 3H), 3.72-3.87 (m, 5H), 4.65 (t, J=5.4 Hz, 2H), 7.15 (dd, J=9.3, 4.2 Hz, 1H), 7.37 (dd, 2H), 7.64 (dd, J=9.2, 3.4 Hz, 1H), 7.77 (dd, J=9.2, 4.4 Hz, 1H), 7.88 (dd, J=8.1, 2.7 Hz, 1H); MS (ESI+) m/z 379 (M+H)+; Anal. Calculated for C18H16F2N2O3S: C, 57.13; H, 4.26; N, 7.40. Found: C, 57.05; H, 4.08; N, 7.35.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 51 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and n-hexyl chloroformate. Yield: 51% of theory, C34H41N7O5 (627.8) Rf value: 0.53 (silica gel; dichloromethane/methanol=9:1) ##EQU82##
Reaction SMILES: C(N)(C)C.[BH4-].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([OH:28])[CH2:15][CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].CS(O[CH2:36][CH2:37][CH2:38][O:39][CH3:40])(=O)=O>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]([O:28][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH2:15][CH2:16][N:17]([CH:25]([CH3:26])[CH3:27])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH:11]=[CH:12][CH:13]=1
Reactant: COCCCOS(C)(=O)=O
Reactant: CC(C)N(CCC(O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)N
Solvent: C1CCOC1
Product: COCCCOC(CCN(C(=O)OC(C)(C)C)C(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(isopropyl)carbamate was obtained using procedures analogous to Preparation A, Steps 1-6, using isopropylamine in Step 1 and NaBH4 in Step 6. To a 0° C. solution of tert-butyl 3-(3-chlorophenyl)-3-hydroxypropyl(isopropyl)carbamate (158 mg, 0.48 mmol) in THF (5 mL) was added NaH (60 mg, 1.45 mmol) and the reaction was allowed to stir for 5 minutes. 3-methoxypropyl methanesulfonate (810 mg, 4.8 mmol) was then added and the reaction was heated to reflux for 2.5 hrs. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride solution at 0° C. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, evaporated and purified via ISCO to afford tert-butyl 3-(3-chlorophenyl)-3-(3-methoxypropoxy)propyl(isopropyl)carbamate. MS ESI+ve m/z 422 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][OH:15])[CH2:9]2)[CH:3]=1.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:23][C:22]1[CH:24]=[CH:25][C:19]([S:16]([O:15][CH2:14][C@H:10]2[O:11][CH2:12][CH2:13][N:8]([C:4]3[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=3)[CH2:9]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CN(c2cc(Br)ccn2)CCO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(c3cc(Br)ccn3)CCO2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
A solution of (S)-(4-(4-bromopyridin-2-yl)morpholin-2-yl)methanol (1.0 equiv.), tosyl chloride (1.0 equiv.), triethylamine (1.40 equiv.) and N,N-dimethylpyridin-4-amine (0.1 equiv.) in dichloromethane (0.1 M) at RT. The resulting mixture was stirred at RT for 18 hours. The reaction mixture was then diluted with water and the aqeuous layer was separated and washed sequentially with NaOH (1 M), water, brine dried over sodium sulfate then concentrated in vacuo to yield (S)-(4-(4-bromopyridin-2-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate in 56% yield. LCMS (m/z) (M+H)=427.1/429.0, Rt=0.77 min.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][NH:21][C:22](=[O:26])[O:23][CH2:24][CH3:25]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][NH:21][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: CCOC(=O)NCCO
Product: CCOC(=O)NCCOC(=N)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and ethyl 2-hydroxy-ethylcarbamate, there is obtained 2-ethoxycarbonylamino-ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a resinous product, mass spectrum m/e: M+ 353 (2), 308 (4), 237 (32), 194 (78), 116 (100), 88 (61);
Reaction SMILES: [Br:1][CH:2]1[CH2:19][C@@:18]2([CH3:20])[C:5]([C:6](Br)([CH2:22]Br)[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])=[CH:4][C:3]1=[O:25].[I-].[Na+]>CC(C)=O>[Br:1][CH:2]1[CH2:19][C@@:18]2([CH3:20])[C:5]([C:6](=[CH2:22])[CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:21])=[CH:4][C:3]1=[O:25]
Reactant: C[C@]12CC(Br)C(=O)C=C1C(Br)(CBr)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC(Br)C(=O)C=C12
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A 250 ml 3-necked round bottomed flask fitted with a condenser, a thermometer and a magnetic stirrer is charged with 2.68 g of 2,6-dibromo-6-bromomethylandrost-4-ene-3,17-dione, 100 ml of acetone and 5.99 g of sodium iodide. The resulting suspension in refluxed for 15 min, cooled to room temperature, filtered and evaporated in vacuo. The residue is taken up with 50 ml of chloroform,washed twice with a saturated sodium thiosulfate aqueous solution, twice with water and dried over anhydrous calcium chloride. Evaporation of the solvent in vacuo yields 1.86 g of the crude title compound which is directly used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COC(=O)c1ccccc1CSc1cc(Cl)ccc1N
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1cc(Cl)ccc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 27.8 %

Procedure:
Following General Procedure B, the title compound (65 mg, 28%) was prepared from methyl 2-(((2-amino-5-chlorophenyl)thio)methyl)benzoate (150 mg, crude) and benzofuran-2-sulfonyl chloride (104 mg, 0.48 mmol) in pyridine (3 ml).