Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][CH2:7][C:8]([OH:10])=O.[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH2:24])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]>CC(N(C)C)=O>[CH3:11][NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16](=[O:30])[C:17]1[C:22]([I:23])=[C:21]([NH:24][C:8](=[O:10])[CH2:7][O:6][CH3:5])[C:20]([I:25])=[C:19]([C:26]([OH:28])=[O:27])[C:18]=1[I:29]
Reactant: COCC(=O)O
Reactant: CNC(=O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CNC(=O)CNC(=O)c1c(I)c(NC(=O)COC)c(I)c(C(=O)O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At maximally 10° C., 29.0 ml. of thionyl chloride is added dropwise under agitation to 28.2 ml. of methoxyacetic acid in 100 ml. of dimethylacetamide within 40 minutes. After, at 0° C., the reaction mixture has been agitated for another 2 hours, 63.0 g. (0.1 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-glycine methylamide (IVa), m.p. 252°-253° C. (decomposition), in 100 ml. of dimethylacetamide is added dropwise under agitation to the reaction mixture at maximally 8° C. during the course of one hour. Then, the solution is agitated overnight. After the addition of 5 ml. of water, the mixture is concentrated under vacuum, the residue is stirred with 700 ml. of water, the precipitate is vacuum-filtered, carefully washed with water, and, while still moist, reprecipitated from dilute ammonia with concentrated hydrochloric acid. After allowing the mixture to stand for some time, the acid is vacuum-filtered, washed well with water, stirred with fresh water, and, after another filtering step, dried under vacuum at 70° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CCOCC.C[C:15]([N:17](C)C)=O>[Cl-].[Na+].O.[Zn].[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]#[N:17])=[N:3][CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(F)cn1
Temperature: 25 °C
Yield: 72 %

Procedure:
2-Bromo-5-fluoropyridine (93.0 g, 528 mmol), Zn dust (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), 1,1′-bis(diphenylphosphino)ferrocene (11.7 g, 21.1 mmol) and Pd2dba3 (9.68 g, 10.6 mmol) in anhydrous DMAc (300 ml) was heated at 95° C. for 3 hours. After cooled to room temperature, brine (100 ml) and ether (500 ml) was added. The solid formed was removed by filtration and washed with ether (300 ml). The organic layer was separated, washed with brine (200 ml) and dried over sodium sulfate, and concentrated. After removal of solvent, the resulted residue was purified by column chromatography (hexane-DCM=1:1) to give the title compound as a white solid (49 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=2.8 Hz, 1H), 8.21 (dd, J=4.4 and 8.8 Hz, 1H), 8.05 (dd, J=2.8 and 8.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:21])[NH:35][CH2:36][C:37](=[O:38])[N:39]([CH3:41])[CH3:40])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:27]=2[N:28]=1)[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)CN
Reactant: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2CCN(C)C(=O)OC(C)(C)C
Yield: 41.1 %

Procedure:
{2-[2-(6-Chloro-benzothiazol-2-ylamino)-5-(dimethylcarbamoylmethyl-carbamoyl)-benzoimidazol-1-yl]ethyl}-methyl-carbamic acid tert-butyl ester (70 mg) was prepared by following General Procedure F starting from 1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (146 mg), 2-amino-N,N-dimethyl-acetamide (50 mg), HBTU (125 mg), and DIEA (100 uL) in DMF (1 mL).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:4].[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=O>O1CCOCC1>[Cl:1][CH2:2][C:3](=[O:4])/[CH:5]=[CH:26]/[C:25]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C=O
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)CCl
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/C(=O)CCl
Reaction time: 1.5 h
Yield: 47.8 %

Procedure:
The mixture of 1-chloro-3-(triphenylphosphoranylidene)acetone (6.6 g) and ethyl glyoxylate (50% in toluene, 4.6 g) in dioxane (66 mL) was stirred at 80′ for 1.5 hour. The solvent was removed by concentration. The residue was purified by column chromatography on silica gel using a mixture of chloroform and hexane (1:1 v/v) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl (2E)-5-chloro-4-oxo-2-pentenoate (1.58 g).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:18](OC([O-])=O)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH2:4]1[C:5]2([CH2:10][CH2:9][N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: C1CCC2(C1)CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a solution of 8-azaspiro[4.5]decane (which has been described in WO 9800404 A1 6.2 g, 44.5 mmol) in dichloromethane (130 ml), which was cooled to 0° C., triethylamine (7.5 ml, 53.4 mmol) was added then a solution of tert-butyl dicarbonate (10.68 g, 48.9 mmol) in dichloromethane (50 ml) was added in 20 minutes. The clear solution was maintained under stirring at room temperature for 18 hours, then dichloromethane (50 ml) was added and the organic solution was washed with water (2×20 ml), HCl 0.1N (20 ml) then water (2×20 ml). The organic solvent was anhydrified (Na2SO4) and evaporated to give a crude that was purified on silica gel column (Hexane/AcOEt 95/5) to give 6 g of the title compound (light yellow solid).
Reaction SMILES: CN(C)[CH:3]=[O:4].S(Cl)(Cl)=O.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18](O)=[O:19].CO>ClCCl>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O:4][CH3:3])=[O:19]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add dimethylformamide (2.1 mL, 27.3 mmol) followed by thionyl chloride (52.3 mL, 717.8 mmol) over 7 minutes to a solution of 2-bromophenylacetic acid (150.0 g, 683.6 mmol) in dichloromethane (1.50 L) cooled with an ambient temperature water bath. Stir mixture for 5 hours, add methanol (41.5 mL, 1.0 mol) over 5 minutes. Bubble nitrogen through solution overnight. Concentrate to obtain the title compound as a colorless oil in quantitative yield (166.0 g, 724.7 mmol). 1H NMR (300 MHz, CDCl3): 7.57 (d, J=7.9 Hz, 1H), 7.30-7.26 (m, 2H), 7.19-7.12 (m, 1H), 3.80 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24](OCC)=[O:25].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][OH:25]
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCCBr
Yield: 101.4 %

Procedure:
According to the method for the synthesis of 206e, 205g (43.0 g, 0.16 mol) was treated with LiBH4 (5.55 g; 0.25 mol) and methanol (7.75 g, 0.24 mol) in CH2Cl2 (200 mL) to give 206g (36.2 g, 98%) as a colorless, viscous oil. 1H NMR (CDCl3): δ 3.41 (t, 2H, J=6.9), 3.30 (br. s, 2H), 1.90-1.84 (m, 3H), 1.42-1.22 (m, 6H), 0.86 (s, 6H). 13C NMR (CDCl3): δ 71.9, 38.6, 35.1, 34.1, 32.9, 29.2, 24.0, 23.2. HRMS (LSIMS, nba): Calcd for C9H18Br (MH+—H2O): 205.0592. found: 205.0563.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][NH:60][C:61]([C@H:63]1[CH2:68][CH2:67][CH2:66][N:65]([CH2:69][C:70](O)=[O:71])[CH2:64]1)=[O:62].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:70](=[O:71])[CH2:69][N:65]1[CH2:66][CH2:67][CH2:68][C@H:63]([C:61]([NH:60][CH3:59])=[O:62])[CH2:64]1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Reactant: CNC(=O)[C@H]1CCCN(CC(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@H]1CCCN(CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide (0.45 g, 0.9 mmol) in anhydrous NMP (10 ml) was treated with HBTU (0.48 g, 1.2 mmol), (S)-2-(3-(methylcarbamoyl)piperidin-1-yl)acetic acid (0.21 g, 1.08 mmol) and diisopropylethyl amine (0.47 mL, 2.7 mmol) with stirring at room temperature overnight. To the reaction was added ethyl acetate (100 mL) and the mixture was washed with aqueous saturated sodium bicarbonate (100 mL×3). The organic layer was dried over magnesium sulfate, filtered and evaporated to an off white solid, 0.34 g that was purified by chromatography (silica gel, ethyl acetate and methanol gradient) to afford (S)-1-(2-(2-((2,4-dichloro-3-((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yloxy)methyl)phenyl)(methyl)amino)-2-oxoethylamino)-2-oxoethyl)-N-methylpiperidine-3-carboxamide (36) as a white solid, 0.12 g (20%), that was about 90 pure by LC/MS (+APCI) m/z 682 (M+), 1HNMR (400 MHz, CDCl3) δ 8.60 (m, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.30 (m, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 7.04 (m, 1H), 6.92 (m, 1H), 6.81 (m, 2H), 6.70 (broad m, 1H), 5.67 (s, 2H), 5.29 (s, 2H), 4.21 (s, 3H), 4.1 to 1.4 (many multiplets, 19H). 13CNMR (100 MHz, CDCl3) δ 174.4, 170.5, 168.8, 156.8, 156.1, 149.6, 149.0, 138.4, 138.2, 137.0, 136.5, 135.8, 135.3, 130.3, 122.6, 121.7, 120.8, 107.3, 103.1, 67.0, 61.6, 57.5, 56.5, 56.2, 54.3, 53.4, 47.7, 45.4, 41.3, 36.0, 30.9, 26.3, 26.1, 24.5.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]3[NH:17][CH:18]=[N:19][C:9]=23)[CH2:3][CH2:2]1.Cl[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][N:22]=1.C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]3[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]4[NH:17][CH:18]=[N:19][C:9]=34)[CH2:3][CH2:2]2)=[N:22][CH:23]=1)#[N:26]
Reactant: NC(=O)c1cnc2[nH]cnc2c1NC1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N2CCC(Nc3c(C(N)=O)cnc4[nH]cnc34)CC2)nc1
Temperature: 90 °C
Yield: 10.9 %

Procedure:
A mixture of 7-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridine-6-carboxamide (46 mg), 6-chloronicotinonitrile (37 mg) and N,N-diisopropylethylamine (46 uL) in NMP (0.5 mL) was heated in the microwave reactor (90° C., 10 minutes). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (20 mL) and half-saturated aqueous sodium hydrogencarbonate (20 mL). The aqueous phase was extracted with EtOAc (2×20 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the product by column chromatography (silica gel, gradient elution, chloroform:methanol=20:1 to 10:1) provided (7 mg) 7-{[1-(5-cyano-2-pyridinyl)-4-piperidinyl]amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].II.C([C:13]1([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)#N>O1CCCC1.BrCCBr>[C:2]1([C:13]2([N:19]3[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(N2CCC(O)CC2)CCCCC1
Reactant: Brc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: OC1CCN(C2(c3ccccc3)CCCCC2)CC1
Reaction time: 17 h

Procedure:
To bromobenzene (4.1 ml) and magnesium turnings (4 g) in 200 ml dry tetrahydrofuran under nitrogen was added a crystal of iodine and 10 drops of 1,2-dibromoethane. After small bubbles began to form, the reaction was stirred and heated to reflux for 4 hours. After cooling to room temperature 1-(1-cyanocyclohexyl)-4-hydroxypiperidine (2 g) was added. After 17 hours, the reaction was filtered, 120 ml saturated ammonium chloride was added and the mixture was extracted with ethyl ether. The ether layer was dried and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1-(1-phenylcyclohexyl)-4-hydroxypiperidine.
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[C:20]1([C:25]([NH:27][NH2:28])=[O:26])[S:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:1][NH:28][NH:27][C:25](=[O:26])[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)=[O:16]
Reactant: NNC(=O)c1cccs1
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (47 mg) in ethanol (1 ml) was added thenohydrazide (27 mg) and the mixture was stirred at room temperature for 1 hour, and then added sodium cyanoborohydride (20 mg) and acetic acid (0.25 ml) and the mixture was stirred for 1 hour. Aqueous sodium bicarbonate was added and extracted with chloroform and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give (2R,4R,5S) -5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane as a residue and the residue was dissolved in methanol (2 ml) and added 1N aqueous sodium hydroxide (0.4 ml) and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was neutralized with 1N hydrochloric acid and extracted with chloroform. The organic layers were combined and dried over sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (ethyl acetate as an eluent) to give (2R,4R,5S)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane (55 mg).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].CC(C)([O-])C.[K+].[C:33]1([CH2:39][O:40][C:41]([N:43]2[CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]2)=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(OCCOCC)C.O1CCCC1.C(OC)(C)(C)C>[C:33]1([CH2:39][O:40][C:41]([N:43]2[CH2:48][CH2:47][CH:46]([CH:7]=[CH:6][CH2:5][C:2]([OH:4])=[O:3])[CH2:45][CH2:44]2)=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CCOCCOCC
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=C(O)CC=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 26 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a suspension of 82 g of 3-carboxypropyl triphenylphosphonium bromide in 407 mL of 1,2-diethoxyethane at 14° C. is added over 25 minutes 220 g of 20 wt % potassium tert-butoxide in tetrahydrofuran while maintaining the reaction mixture temperature at 24-28° C. The mixture is stirred for 1 hour, cooled to 10° C., and a solution of 52.5 g of 1-phenylmethoxycarbonyl-4-piperidone in 246 mL of methyl tert-butyl ether is added over 30 minutes while maintaining cooling. After addition is complete, the mixture is stirred at 12° C. for 10 minutes, then warmed to 20° C. and stirred for an additional 30 minutes. The reaction mixture is treated with 410 mL of 1N aqueous HCl for 10 minutes, diluted with 328 mL of methyl tert-butyl ether, and then the phases are separated. The organic phase is washed with 205 mL of water, then 210 mL of 1N aqueous NaOH. The NaOH layer, which contains the product, is collected separately, washed with three 189 g portions of ethyl acetate, acidified to pH 3.48 with concentrated HCl, then extracted with 189 mL of ethyl acetate. The ethyl acetate layer is separated, washed with 211 mL of water, then dried for 30 minutes over 10 g of MgSO4, filtered, and concentrated in vacuo. The oily residue (50.7 g) is crystallized from toluene/heptane to afford a total of 29.46 g (51% yield) of 3-(1-phenylmethoxycarbonyl-4-piperidinylmethylene)propanoic acid. Mass Spec: Mcalc. 303, M+1obsvd 304. 1H NMR: (δ vs TMS, CDCl3) 2.2, t (2H); 2.25, t (2H); 2.35, m (4H); 3.45, m (4H), 5.15, s (2H); 5.2, m (1H); 7.33, 2 (5H). 13C NMR (δ vs TMS, CDCl3) 22.43, 28.2, 34.26, 35.66, 44.88, 45.74, 67.20, 122.02, 127.83, 127.95, 128.45, 128.69, 128.90, 136.17, 136.72, 155.34, 178.39
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26]([NH:29][C@@H:30]([C:32]([OH:34])=O)[CH3:31])(=[O:28])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1.ClCCl>[C:26]([NH:29][CH:30]([CH3:31])[C:32]([N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)=[O:34])(=[O:28])[CH3:27]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CC(=O)N[C@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NC(C)C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), N-acetyl-D-alanine (7 mg, 0.053 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13 mg, 0.068 mmol), 1-hydroxybenzotriazole (9 mg, 0.068 mmol), dichloromethane (1 mL) and THF (0.5 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column which was eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (13 mg, 65% yield).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([OH:38])=O)[CH2:30][CH2:29]1.CS(N)(=O)=O.[N:57]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1>>[N:57]1([S:61]([NH:64][C:36](=[O:38])[C:35]2[CH:39]=[C:31]([CH:28]3[CH2:29][CH2:30]3)[C:32]([O:41][CH2:42][C:43]34[C:49]([F:51])([F:50])[CH:48]3[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:33][C:34]=2[F:40])(=[O:63])=[O:62])[CH2:60][CH2:59][CH2:58]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-(((1RS,6SR)-7,7-difluorobicyclo-[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a white gum (0.040 g, 30%): 1H NMR (300 MHz, DMSO-d6) δ 11.61 (br s, 1H), 7.14 (d, J=8.25 Hz, 1H), 6.92 (d, J=12.76 Hz, 1H), 4.17-3.92 (m, 6H), 2.21-2.05 (m, 2H), 2.04-1.54 (m, 6H), 1.36-1.14 (m, 4H), 0.92-0.80 (m, 2H), 0.72-0.63 (m, 2H); MS (ES+) m/z 459.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][Cl:14])[CH:10]([CH2:15][Cl:16])[CH2:9][N:8]=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][Cl:14])[CH:10]([CH2:15][Cl:16])[CH2:9][N+:8]([O-:31])=[C:7]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:6]=2[CH:22]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccco2)=NCC1CCl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccco2)c2cc(Cl)ccc2N(CCCl)C(CCl)C1
Yield: 69.9 %

Procedure:
A solution of 17.8 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine in 250 ml of methylene chloride is heated under reflux with 10.4 g of 3-chloroperbenzoic acid for 2-hours. The reaction solution is then rendered alkaline with aqueous dilute sodium hydroxide solution and is worked upon in the customary manner, and the reaction product is isolated and then purified by chromatography on aluminium oxide of activity level II, using methylene chloride, and crystallised from methanol. 13 g of 7-chloro-1-(β-chloroethyl)- 2-chloromethyl-5-(2-furyl)-2,3-dihydro-1H-1,4-benzodiazepine 4-oxide are obtained. Melting point: 158° to 159° C.