Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN[N:3](NC)[C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](CC)=[C:7]([N+:16]([O-:18])=[O:17])[C:6]=1Cl.Cl.[Cl:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][Cl:30].[CH3:31][CH2:32][N:33]([CH2:36]C)[CH2:34]C>>[CH3:34][N:33]([CH2:32][CH2:31][NH:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([N+:16]([O-:18])=[O:17])[C:6]=1[N:27]([CH2:28][CH2:29][Cl:30])[CH2:26][CH2:25][Cl:24])[CH3:36]
Reactant: CCc1c([N+](=O)[O-])cc(C(=O)N(NC)NC)c(Cl)c1[N+](=O)[O-]
Reactant: ClCCNCCCl
Reactant: CCN(CC)CC
Agent: Cl
Product: CN(C)CCNC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1N(CCCl)CCCl

Procedure:
Reaction of this amide (XI: Z=NHCH2CH2NMe2) with bis(2-chloroethyl)amine hydrochloride and Et3N as above, followed by chromatography on silica gel and elution with EtOAc/MeOH (9:1) gave N-(N,N-dimethylaminoethyl) 2-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzamide (20 ) (Ie: R=CONHCH2CH2NMe2), mp (EtOAc/petroleum ether) 115°-118° C. 1H NMR (CDCl3) δ 8.63 (s, 2 H, ArH4), 7.41 (br, 1 H, CONH), 3.74 (t, J=6.3 Hz, 4 H, CH2Cl), 3.59 (t, J=5.8 Hz, 2 H, CONHCH2), 3.55 (t, J=6.3 Hz, 4 H, NCH2CH2Cl), 2.56 (t, J=5.8 Hz, 2 H, CH2NMe2), 2.27 (s, 6 H, NMe2). 13C NMR 164.70 (CO), 145.93 (C-2), 144.86, 141.94 (C-3,5), 135.68 (C-1), 129.63 (C-4), 123.16 (C-6), 57.51 (CONHCH2), 54.82 (NCH2CH2Cl), 45.12 (NMe2), 41.39 (NCH2CH2Cl), 37.67 (CONHCH2). Anal. (C15H21Cl2N5O5) C,H,N,Cl. (The hydrochloride salt was too hygroscopic to handle).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:29]=[C:30]([N:34]5[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]5)[CH:31]=[CH:32][CH:33]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:42]1([C@@H:48]2[CH2:52][CH2:51][NH:50][CH2:49]2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:50]4[CH2:51][CH2:52][C@@H:48]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:49]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:29]=[C:30]([N:34]3[S:38](=[O:40])(=[O:39])[NH:37][C:36](=[O:41])[CH2:35]3)[CH:31]=[CH:32][CH:33]=2)[CH:17]=1
Reactant: c1ccc([C@@H]2CCNC2)cc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CC[C@@H](c6ccccc6)C5)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (134 mg, 0.2 mmol) was treated as described in general procedure R using excess (S)-3-phenyl-pyrrolidine (147 mg, 1 mmol) to give the desired compound 5-(3-{4-(2,4-dichloro-phenyl)-2-{4′-[(3S)-3-phenyl-pyrrolidin-1-yl]-biphenyl-4-ylmethyl}-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[O:18][C:17]=2[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)=[O:12]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:9][O:10][C:11]([C:13]1[C:21]2[CH:20]=[C:19]([CH2:22][Br:1])[O:18][C:17]=2[C:16]([O:23][CH3:24])=[CH:15][CH:14]=1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC)c2oc(C)cc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)c2oc(CBr)cc12
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a well stirred refluxing solution of AIBN (40.0 mg, 1.0%) and N-bromo succinimide (3.4 g, 19.05 mmol) in carbon tetrachloride (60.0 mL) was added a Methyl-7-methoxy-2-methylbenzo[b]furan-4-carboxylate (from step 5) (4.0 g, 18.16 mmol) and refluxed for 2-3 hours. Reaction mixture was cooled to room temperature and filtered thorough Celite bed. The filtrate was concentrated under vacuo to give product (3.1 g) as brown oil. The product obtained was taken ahead for next step without further purification.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH:16]1[CH:17]=[CH:18][C:19]2N(O)N=[N:22][C:20]=2[CH:21]=1.CCN(C(C)C)C(C)C.[CH3:35][C:36]1[CH:37]=[C:38]([CH2:43][C:44]([NH:46][CH:47]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:48](O)=[O:49])=[O:45])[CH:39]=[C:40]([CH3:42])[CH:41]=1.[N:58]1[C:59](NC2C=CC=CC=2)=[CH:60][N:61]2[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[S:63][C:62]=12>C(Cl)Cl>[CH3:42][C:40]1[CH:39]=[C:38]([CH2:43][C:44]([NH:46][C@@H:47]([CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:48]([NH:22][C:20]2[CH:21]=[CH:16][C:17]([C:59]3[N:58]=[C:62]4[N:61]([CH:60]=3)[C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=3[S:63]4)=[CH:18][CH:19]=2)=[O:49])=[O:45])[CH:37]=[C:36]([CH3:35])[CH:41]=1
Reactant: On1nnc2ccccc21
Reactant: c1ccc(Nc2cn3c(n2)sc2ccccc23)cc1
Reactant: Cc1cc(C)cc(CC(=O)NC(Cc2ccccc2)C(=O)O)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)cc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2ccc(-c3cn4c(n3)sc3ccccc34)cc2)c1

Procedure:
BOP-Cl (114.5 mg, 0.450 mmol), HOBT (33.4 mg, 0.247 mmol) and DIPEA (157 μl, 0.899 mmol) were added to a solution of (S) 2-[2-(3,5-dimethylphenyl)acetamido]-3-phenyl-propanoic acid (70.0 mg, 0.225 mmol) in dry CH2Cl2 (10 ml). After 10 min 4-[(imidazo[2,1-b]benzothiazol-2-yl)aniline (65.1 mg, 0.247 mmol) was added to the solution and the reaction mixture was reflux under nitrogen for 6 h. The solvent was removed under reduced pressure and the crude mixture was purified by flash chromatography (MeOH 2.5%-CH2Cl2 97.5%) to afford the desired product (S)-2-(3,5-dimethylphenylacetamido)-3-phenyl-N-[4-(imidazo[2,1-b]benzothiazol-2-yl)phenyl]propanamide as a yellow solid (42% c.y.).
Reaction SMILES: [C:1]1([CH2:11][C:12](=[CH2:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[SH:25][CH2:26][CH2:27][OH:28]>C(OCC)C>[OH:28][CH2:27][CH2:26][S:25][CH2:18][CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: OCCS
Reactant: C=C(Cc1cccc2ccccc12)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(CSCCO)Cc1cccc2ccccc12
Temperature: 25 °C

Procedure:
2.04 g of ethyl 2-(1-naphthyl)methyl-2-propenoate was dissolved in 714 μl of 2-mercaptoethanol, and 102 mg of potassium tert-butoxide was added thereto at room temperature under stirring. The mixture was stirred at room temperature for 15 minutes. 500 μl of 2-mercaptoethanol was added thereto and the mixture was stirred for 15 minutes. Then, the reaction solution was diluted with 150 ml of diethyl ether. The diethyl ether layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 2.81 g of ethyl (2RS)-3-(2-hydroxyethyl)thio-2-(1-naphthylmethyl)propionate as colorless oily substance.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 73A (0.28 g, 0.441 mmol) in a mixture of THF (5 mL), methanol (5 mL), and aqueous HCl (5 mL, 1 N) was stirred at 60° C. for 16 hours, and concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)(=O)C.CCOCC>C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][CH:28]([CH:25]=[C:1]([Br:5])[Br:2])[CH2:29][CH2:30]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=C(Br)Br)CC1
Reaction time: 0.67 h
Yield: 79.8 %

Procedure:
A solution of 48.615 g (146.6 mmole) carbon tetrabromide in 150 mL DCM was added dropwise with stirring to a solution of 76.895 g (293.2 mmole) triphenylphosphine in 150 mL DCM in a 1-L rb flask with ice bath cooling over 1.75 hours. After 40 minutes, a solution of 15.631 g (73.29 mmole) 1-(t-butoxycarbonyl)-4-formyl-piperidine (from Step 2 above) in 100 mL DCM was added to the resulting brown suspension with stirring and cooling over 40 minutes. After one hour, 200 mL ether and 400 mL hexanes was added. The top suspension was filtered through Celite, and the residue was resuspended in 150 mL DCM and treated with 300 mL ether. The mixture was filtered, and the solid was washed with hexanes till total filtrate was 2 L. The filtrate was filtered again through Celite and washed with hexanes. The filtrate was washed with 100 mL 5% NaHCO3, 300 mL water (2×), and 150 mL brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 53.458 g crude product as a yellowish solid. Flash chromatography (PC) on 250 g silica gel (0-15% EtOAc in hexanes) gave 21.595 g title compound as a white solid. RF: 0.57 (15% EtOAc in hexanes); 1H NMR (500 MHz) δ 6.25 (d, J=8.9 Hz, 1H), 4.04-4.12 (m, 2H), 2.75-2.83 (m, 2H), 2.42-2.50 (m, 1H), 1.69-1.75 (m, 2H), 1.47 (s, 9H), 1.29-1.37 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH2:39])=[N:36][C:35]=1[CH3:40])(=[O:33])=[O:32]>>[OH:27][CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:38][C:37]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:36][C:35]=1[CH3:40])(=[O:32])=[O:33]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NCCO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NCCO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (example B.10) according to general procedure II. Yellow solid, MS (ISP) 593.1 [(M−H)−]; mp 166° C.
Reaction SMILES: C([O:3][C:4]([C@:6]1([CH3:31])[CH2:10][C@@H:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[N:8](C(=O)C(C)(C)C)[C:7]1=[O:30])=[O:5])C.[OH-].[Na+]>C(#N)C>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([CH2:11][C@H:9]2[NH:8][C:7](=[O:30])[C@:6]([CH3:31])([C:4]([OH:5])=[O:3])[CH2:10]2)=[CH:17][CH:16]=1.[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:12]([CH2:11][C@H:9]2[NH:8][C:7](=[O:30])[C@@:6]([CH3:31])([C:4]([OH:5])=[O:3])[CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)[C@]1(C)C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: C[C@@]1(C(=O)O)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Product: C[C@]1(C(=O)O)C[C@@H](Cc2ccc(-c3ccccc3)cc2)NC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
252 mg (3R,5R)-5-Biphenyl-4-ylmethyl-1-(2,2-dimethylpropionyl)3-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (R1=Piv; R10=OEt; R11=Me) [62:38 mixture of C3-isomers] is added to 1 ml acetonitrile at 0° C. 0.3 ml 3 M Sodium hydroxide solution is added and the mixture stirred at room temperature for 20 h. Two further 50 μl portions of 3 M sodium hydroxide are added. Stirring is continued for another 2 h. The mixture is concentrated in vacuo. 2.5 ml of water is added to the residue and it is then extracted twice with 1 ml toluene. 5 ml Ethyl acetate is added to the aqueous phase, which is then cooled to 0° C. 500 μl 2 M Hydrochloric acid is added and the phases are separated. The aqueous phase is then extracted with ethyl acetate. The combined organic phases are combined, dried (MgSO4) and concentrated in vacuo to afford (3R, 5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid (R1=H; R10=OH; R11=Me) and (3S,5R)-5-Biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-3-carboxylic acid (R1=H; R10=OH; R11=Me). According to HNMR analysis there is a 66:34 mixture of C3-stereoisomers. Identity of major isomer not determined. 1H NMR (DMSO) [mixture of stereoisomers]: 1.21 (3H), 1.59, 1.84, 2.20, 2.29 (total 2H), 2.66 (1H), 2.93 (1H), 3.81 (1H), 7.31 (3H), 7.44 (2H), 7.60 (4H), 8.10, 8.15 (total 1H), 12.58 (1H).
Reaction SMILES: [C:1]([C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[CH:24]1([CH2:23][C@H:10]2[C@H:9]([C@@H:1]([OH:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:13][C:12]([CH3:15])([CH3:14])[N:11]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)c2ccccc2)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@@H](O)c2ccccc2)OC1(C)C
Yield: 20.6 %

Procedure:
290 mg (0.72 mmol) of t-butyl (4S,5R)-5-benzoyl-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate in 5 ml of methanol are stirred at room temperature for 1 hour with 27 mg (0.7 mmol) of sodium borohydride. Thereafter, the reaction mixture is treated with two drops of glacial acetic acid and evaporated to dryness. The residue is chromatographed on 30 g of silica gel with a 4:1 mixture of hexane and ether as the eluting agent, with a methylene chloride solution of the crude product being applied to the column. In this manner there are obtained 60 mg of t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(S)-α-hydroxybenzyl]-2,2-dimethyl-3-oxazolidinecarboxylate as a white solid, MS: 403 (M)+, as well as 210 mg of the epimeric t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-α-hydroxybenzyl]-2,2-dimethyl-3-oxazolidinecarboxylate also as a white solid, MS: 403 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[C:11](=[O:14])([O-:13])[O-].[K+].[K+].[CH3:17]I>C(#N)C.ClCCl>[CH3:10][C:2]1([CH3:1])[O:13][C:11](=[O:14])[C:6]([CH3:17])([CH3:4])[C:7](=[O:8])[O:9]1
Reactant: CI
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)OC(=O)C(C)(C)C(=O)O1
Temperature: 75 °C

Procedure:
A mixture of Meldrum's acid (5.52 g, 38.3 mmol), potassium carbonate (26.5 g, 191 mmol) and methyl iodide (7.15 mL, 115 mmol) in acetonitrile (75 mL) was heated at 75° C. in a sealed tube for 7 hrs. The mixture was cooled to room temperature, diluted with dichloromethane (300 mL), filtered and the filtrate evaporated to dryness in vacuo. Ethyl acetate (75 mL), hexanes (75 mL) and water (50 mL) were added and phases were separated. The organic layer was washed with 10% aqueous solution of sodium thiosulfate (50 mL) and water (50 mL); dried over anhydrous magnesium sulfate and solvent removed in vacuo to give 2,2,5,5-tetramethyl-[1,3]dioxane-4,6-dione as white solid.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[C:8]([F:31])[CH:7]=1.[Cl:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:2]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[C:8]([F:31])[CH:7]=2)=[CH:42][CH:41]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3Br)cc1F)n2C1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc([N+](=O)[O-])ccc3-c3ccc(Cl)cc3)cc1F)n2C1CCCCC1
Yield: 90.1 %

Procedure:
Methyl 2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylate (2.0 g) obtained in Example 336, 4-chlorophenylboronic acid (590 mg) and tetrakis(triphenylphosphine)palladium (396 mg) were suspended in dimethoxyethane (40 ml), and saturated aqueous sodium hydrogencarbonate solution (20 ml) was added, which was followed by refluxing under heating for 1 hr. The reaction mixture was allowed to cool, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (n-hexane:ethyl acatate=2:1) to give the title compound (1.9 g, yield 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[N:39][CH:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[N:39][CH:38]=[N:37]2)[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ncnc2COC2CCCCO2)c1
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ncnc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J8) (1.0 g, 3.19 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,4]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K24) (1.28 g, 3.19 mmol) according to the general procedure M. Obtained as a yellow foam (1.48 g).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].CCN(CC)CC.[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=1.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([CH2:23][O:24][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[CH:20]=[CH:21][CH:22]=1
Reactant: OCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
TBSCl (18.7 g, 124.3 mmol), Et3N (14.08 g, 139.2 mmol) and DMAP (194.3 mg, 8.9 mmol) were dissolved in CH2Cl2 (120 mL), then the solution was cooled to 0-5° C. (3-bromophenyl)methanol (18.5 g, 99.4 mmol) was added dropwise to the solution. After the addition, the mixture was warmed to room temperature, and stirred for 2 h. 5% HCl was added to the reaction mixture to pH=4-5, then the organic phase was separated, and the aqueous layer was extracted with CH2Cl2 (50 mL×2). The combined organic phase was washed with water, and dried over Na2SO4. After removing the solvent, 28.5 g of {[(3-Bromophenyl)methyl]oxy}(1,1-dimethylethyl)dimethylsilane was obtained (Yield: 95.1%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[NH:23][CH2:22][CH2:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][C:18]=3[CH:28]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[CH2:29]([O:31][CH2:32][CH2:33][CH:34]=O)[CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][N:23]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:1][CH2:2][CH3:3])=[CH:9][CH:10]=3)=[CH:28][C:18]=2[CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]1)[CH3:30]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CCOCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Reaction time: 20 h
Yield: 96.9 %

Procedure:
To a solution of methyl 7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (400 mg) and 3-ethoxypropionaldehyde (0.53 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.66 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction system was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate:hexane=1:4→1:3) to give methyl 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (475 mg) as yellow oil.
Reaction SMILES: [Br-].[N:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[N+:3]=[N-:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:37]([O:41][C:42](=[O:60])[NH:43][CH2:44][CH2:45][CH2:46][O:47][C:48]1[C:57]2[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=2[C:51]([CH:58]=O)=[CH:50][CH:49]=1)([CH3:40])([CH3:39])[CH3:38].O>C1COCC1>[C:37]([O:41][C:42](=[O:60])[NH:43][CH2:44][CH2:45][CH2:46][O:47][C:48]1[C:57]2[CH2:56][CH2:55][CH2:54][CH2:53][C:52]=2[C:51]([CH:58]=[CH:7][CH2:6][CH2:5][N:2]=[N+:3]=[N-:4])=[CH:50][CH:49]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2c1CCCC2
Reactant: [N-]=[N+]=NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=CCCN=[N+]=[N-])c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
(3-Azido-propyl)-triphenylphosphonium bromide (112, 11.5 g, 27 mmol) was stirred with 100 mL of dry THF at −76° C. LiHMDS (0.5 M in toluene, 27 mL) was added and the mixture was stirred for 30 minutes. [3-(4-Formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (111, 6 g, 18 mmol) in 12 mL dry THF solution was introduced. The reaction mixture was stirred at this temperature for another 30 minutes, and slowly warmed to room temperature. The mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, concentrated, and purified by flash chromatography (0-25% EtOAc/Hexane) to give 3.5 g 113 {3-[4-(4-azido-but-1-enyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-propyl}-carbamic acid tert-butyl ester.