Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1.[CH2:35]([N:37](CC)[CH2:38]C)[CH3:36]>C(Cl)Cl>[Cl:11][C:12]1[CH:25]=[CH:24][C:23]2[CH:22]3[CH2:26][C:15]([CH2:27][N:28]4[CH2:29][CH2:30][C:31]([C:36]5[CH:35]=[N:37][CH:38]=[CH:1][CH:2]=5)([OH:34])[CH2:32][CH2:33]4)([C:16]4[C:21]3=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=2[CH:13]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC1(c2cccnc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (3.06 mL, 35.1 mmol, 2 eq) in methylene chloride (100 mL) under nitrogen was added distilled dimethylsulfoxide (5.00 mL, 70.2 mmol, 4 eq). After 10 min 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl) piperidin-4-ol (described in example 11) (5.96 g, 17.5 mmol) was added as a methylene chloride solution (10 mL). The reaction was stirred at -78° C. for 30 min prior to the addition of triethylamine (19.6 mL, 140 mmol, 8 eq). The cooling bath was removed and the reaction warmed to room temperature over 1.5 h. The reaction was poured into 2.5N NaOH (100 mL) and the aqueous phase extracted with methylene chloride (3×100 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The crude reaction mixture was purified by flash chromatography over silica gel (400 mL, eluent: 20% ethyl acetate in hexane) to yield 5.53 g (93%) of the title compound. TLC analysis (Rf 0.21, 20% ethyl acetate in hexane). 1H NMR (CDCl3, 250 MHz) 7.26 (m, 1H), 7.13 (m, 3H), 6.95 (m, 3H), 4.28 (s, 1H), 3.49 (s, 2H), 2.94 (t, J=6.1 Hz, 4H), 2.62 (s, 2H), 2.43 (t, J=6.0 Hz, 4H) MS (CI, CH4) m/z 338 (M+1,100), 340 (35), 366 (M+29,31).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][C:18](=[CH:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:16][CH2:17][C:18](=[CH:21][C:22]([OH:24])=[O:23])[CH2:19][CH2:20]1
Reactant: COCOc1ccc(C2CCC(=CC(=O)O)CC2)c(OCOC)c1
Solvent: CO
Product: O=C(O)C=C1CCC(c2ccc(O)cc2O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 35.2 %

Procedure:
A round bottomed flask was charged with (±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetic acid (25 mg), acidic Dowex resin (75 mg) and methanol (15 ml) then stirred at 60° C. for 3 hr. The reaction mixture was filtered through a celite plug, washing with methanol. The solvent was removed under reduced pressure to give an oil which was purified by preparative TLC (ethyl acetate/petroleum ether, 3:1, v/v), furnishing the title compound (6.5 mg, 35%) as an oil. δH(CD3OD) 1.22-1.40 (2H, m), 1.90-2.10 (4H, m), 2.36-2:40 (2H, m), 3.08 (1H, tt), 5.62 (1H, s), 6.20 (1H, dd), 6.25 (1H, d), 6.84 (1H, d); m/z (ES+) 339 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:26][C:27]([CH3:31])([CH3:30])[CH2:28][OH:29])=[O:20])=[CH:17][N:16]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)NC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 6-[3-(4-chloro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.28 mmol) and 2-amino-2-methyl-1-propanol (25.5 mg, 0.28 mmol) in THF (10 mL) were added at 0° C., 1-hydroxybenzotriazole hydrate (43.3 mg, 0.28 mmol), N-ethyldiisopropylamine (121 μL, 0.69 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (54.2 mg, 0.28 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation. The remaining material was purified by chromatography (silica, dichloromethane:methanol=99:1 to 95:5) to afford the title compound (91 mg, 76%) as a white solid. MS: m/e=430.1 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1.COC(=O)C(O)C(C)C.[C:35]([O:39][C:40](=[O:45])[C@@H:41](O)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36].CO>C(OCC)(=O)C>[C:35]([O:39][C:40](=[O:45])[C@H:41]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH2:3][C:2]([F:24])([F:1])[F:25])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH2:42][CH3:43])([CH3:38])([CH3:37])[CH3:36]
Reactant: Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Agent: COC(=O)C(O)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC[C@@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C

Procedure:
Following the procedure for Example 426, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol, 2-hydroxy-3-methyl-butyric acid methyl ester and (S)-2-hydroxy-butyric acid tert-butyl ester were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-10% methanol in ethyl acetate) to give (R)-2-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester as a yellow oil contaminated with triphenylphosphine oxide. LCMS: RT=4.05 min, [M+H]+=494
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:6]([F:22])[C:5]=1Cl)(=[O:3])[CH3:2].[N-:24]=[N+]=[N-].[Na+]>CC(C)=O.O>[F:22][C:6]1[C:5]2[C:4](=[C:1]([CH3:2])[O:3][N:24]=2)[N:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[C:7]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21]
Reactant: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1nc2c(C)onc2c(F)c1Nc1ccccc1F
Temperature: 65 °C

Procedure:
To a solution of methyl 6-acetyl-5-chloro-4-fluoro-3-(2-fluorophenylamino)picolinate (WO 2005/051906) (2 g, 5 mmole) in a mixture of acetone (36 ml) and H2O (12 ml) is added NaN3 (487 mg, 7.5 mmol). The reaction is heated at 65° C. for 16 h and cooled to room temperature. Acetone is concentrated and the resulting mixture is extracted with EtOAc (2×50 ml). The combined organic solution is washed with brine (50 ml), dried over MgSO4 and concentrated to give a yellow solid. To the solid is added H2O (24 ml) and the reaction is heated at reflux for 3 h. The reaction is cooled to room temperature, filtered, and washed with H2O. The resulting solid is dried under high vacuum with P2O5 at 65° C. for 24 h to give the title compound.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)[C:31](F)=[CH:30][N:29]=1.NC1C=C2C(=CC=1)NC=C2>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[C:22]5[C:23](=[CH:24][CH:25]=4)[NH:29][CH:30]=[CH:31]5)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Nc1ccc2[nH]ccc2c1
Product: Fc1cnc(Nc2ccc3[nH]ccc3c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 5-aminoindole were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 20.37 min.; purity: 97%; MS (m/e): 378 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH2:39][C:40]([N:26]1[CH2:27][CH2:28][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([NH:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:24][CH2:25]1)=[O:41]
Reactant: O=C(Nc1ccccc1)c1ccccc1N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)c1ccccc1N1CCN(C(=O)CCl)CC1
Temperature: 4 °C
Reaction time: 2 h
Yield: 666.4 %

Procedure:
4-(2-phenylcarbamoyl-phenyl)-piperazine trifluroacetate (0.454 g, 1.150 mmol) is dissolved in 10 mL of CH2Cl2 containing diisopropylethyl amine (0.554 mL, 3.000 mmol). The mixture is cooled to 4° C. and chloroacetyl chloride (0.105 mL, 0.130 mmol) is added in a dropwise fashion. The reaction is stirred for 2 h in ice bath and then quenched with 20 mL of saturated NH4Cl. The reaction is diluted with 100 mL EtOAc and washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The crude product is purified via a SiO2 column and (0-75% EtOAc/hexanes) to give 310 mg of 2-[4-(2-chloro-acetyl)-piperazin-1-yl]-N-phenyl-benzamide in 75% yield.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[NH2:7][C:8]1[CH2:13][CH2:12][CH:11](I)[C:10](=[O:15])[C:9]=1[CH3:16].S(OC)(OC)(=O)=O>C1COCC1>[CH3:1][O:15][C:10]1[C:9]([CH3:16])=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC1=C(N)CCC(I)C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COc1cccc(N)c1C
Temperature: -15 °C
Yield: 89 %

Procedure:
2.24 g (20 mmol, 2 eq) of potassium tert-butoxide is dissolved in 60 ml of anhydrous THF and the resulting solution is cooled to −15° C. with stirring. A solution of 2.51 g (10 mmol, 1 eq) of 3-amino-6-iodo-2-methyl-2-cyclohexen-1-one in 25 ml anhydrous THF is added to the potassium tert-butoxide solution and the temperature is kept below −5° C. during addition. The cooling bath is removed after addition and the reaction is allowed to warm up to 5° C. within 1 hour. HPLC shows complete elimination. 1.20 g (9.5 mmol, 0.95 eq) of dimethyl sulfate is added to the reaction mixture with vigorous Stirring. The reaction is shown to be complete by HPLC (˜2 h). Then an HPLC weight assay indicates an 89% yield of the product. The isolation of the product was not optimized.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22]C(=O)C)=[C:15]([O:26]C(=O)C)[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.O>CO>[C:1]12([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([OH:26])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)Oc1cc(C(=O)NC23CC4CC(CC(C4)C2)C3)cc([N+](=O)[O-])c1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 88.8 %

Procedure:
A solution containing 1.2 g of the product obtained in Example 43 and a catalytic amount of sulfuric acid in 10 ml of methanol was refluxed for 3 h. 20 ml of water was added and on cooling 0.85 g (89.5%) of the desired product was crystallized, m.p. 207°-208° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)O[C:12](=O)[C:11]2[CH:10]=C[CH:8]=[CH:7][C:6]1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:34][C@@H:33]([CH3:35])[C@H:32]([OH:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[CH3:10][CH:11]([CH2:6][CH2:7][CH3:8])[CH3:12].[C:23]([O:27][C:28]([N:30]1[CH2:31][C:32](=[O:36])[CH:33]([CH3:35])[CH2:34]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1CN(C(=O)OC(C)(C)C)CC1=O
Product: CCCC(C)C
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Cool down a suspension of Dess Martin periodinane (1.1 g, 2.6 mmol) in dry dichloromethane (5 mL) under nitrogen with an ice bath and add a solution of trans-3-hydroxy-4-methylpyrrolidine-1-carboxylic acid tert-butyl ester (350 mg, 1.73 mmol) in dry dichloromethane (2 mL). Stir under nitrogen and allow to warm up to room temperature overnight. Add saturated aqueous sodium hydrogen carbonate, then saturated aqueous sodium thiosulfate and extract with dichloromethane. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and chromatograph on silica gel, eluting with 0:100 to 40:60 ethyl acetate:2-methylpentane to give 3-methyl-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 4.06-4.19 (1H, m), 3.84-3.98 (1H, m), 3.61-3.72 (1H, m), 3.17 (1H, dd, J=11.11, 9.04 Hz), 2.56-2.70 (1H, m, J=7.72 Hz), 1.49 (9H, s), 1.18 (3H, d, J=7.16 Hz), MS (ES): m/z=222 [M+Na].
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:14]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[C:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[CH:13]2)[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Product: c1cnc2c(c1)c(C1CCNCC1)cn2CC1CC1

Procedure:
This compound was prepared following the procedure described in example 24, parts C and D, starting with 0.3 g (1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.175 g (1.23 mmol) of bromomethylcyclopropane. After standard work-up, 0.242 g (96% of yield) of the expected product were isolated.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([C:14](=O)[CH3:15])=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:17][C:18]([NH2:20])=[S:19]>CCO.CCOC(C)=O>[CH2:1]([O:3][P:4]([C:9]1[S:10][C:11]([C:14]2[S:19][C:18]([NH2:20])=[N:17][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOP(=O)(OCC)c1ccc(C(C)=O)s1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccc(-c2cnc(N)s2)s1
Temperature: 25 °C
Yield: 15.9 %

Procedure:
To a solution of (5-acetyl-thiophen-2-yl)-phosphonic acid diethyl ester (1.13 g, 4.31 mmol) in EtOH (80 ml) was added CuBr2 (959 mg, 8.62 mmol). The reaction mixture was then refluxed for 3 hr, diluted with EtOAc, quenched by adding sat. NaHCO3. After layers were separated, the org. layer was collected and the aqueous layer was further extracted with EtOAc once. Combined organic layers were dried over MgSO4, filtrated, and concentrated. The residue was then dissolved in EtOH/EtOAc (4 ml/16 ml) and treated with thiourea (394 mg, 5.17 mmol). The reaction mixture was then heated to reflux for 1 hr, cooled to r.t., and concentrated down. The residue was partitioned between EtOAc and water. The organic layer was collected, dried over MgSO4, filtrated, concentrated, and purified by Biotage to give the final compound (218 mg, 15.9%). 1H NMR (300 MHz, DMSO-d6): δ 7.50 (m, 2H), 7.23 (s, 2H), 7.10 (s, 1H), 4.02 (m, 4H), 1.21 (m, 6H). LC-MS m/z=263.4 [C7H7N2O3PS2+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: BrCc1ccccc1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (1 g, 4.95 mmole) was dissolved in acetonitrile (200 ml) and NaOH (198 mg, 4.95 mmole) was added. After stirring for 1 hr at room temperature, benzyl bromide (0.589 ml, 4.95 mmole) was added and the mixture was allowed to stir overnight. The mixture was concentrated under reduced pressure and purified on a silica gel column (3.5×5 cm) using 5% MeOH/CHCl3 to give 1.23 g (85%) of 2-amino-1-benzyl-5,6-dichlorobenzimidazole (182). The compound was then recrystallized from EtOH/H2O to give a white powder. 1H NMR (DMSO-d6): d 5.28 ppm (s, 2H), 6.95 (s, 2H), 7.16 (d, 2H), 7.25 (d, 1H), 7.31 (m, 4H). 13C NMR (DMSO-d6): d 44.74 ppm, 109.15, 115.37, 119.62, 122.66, 126.82, 127.37, 128.55, 134.10, 136.46, 143.13, 156.91. MS (Electron Impact): m/e 291, 200, 158, 91, 65. MP: 245-246° C. Elemental Analysis: (C14H11Cl2N3'): Calculated: C, 57.55; H, 3.79; N, 14.38. Found: C, 57.66; H, 3.83; N, 13.98. UV Imax nm (e×104): (pH 7) 230 (0.761), 260 (0.324), 302 (0.452); (pH 1) 238 (0.306), 294 (0.383), 299 (0.359); (pH 11) 229 (0.869), 257 (0.316), 301 (0.443).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:41]1([P:47](Cl)(=[O:55])[O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([P:47](=[O:55])([O:32][C:30]([CH3:31])=[C:16]([N:13]2[C:12](=[O:33])[CH:11]3[CH:14]2[S:15][C:9]([CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:10]3)[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=P(Cl)(Oc1ccccc1)c1ccccc1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(OP(=O)(Oc1ccccc1)c1ccccc1)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0° C. was added triethylamine (1.6 ml.) followed by phenyl phenylphosphonochloridate (2.91 g). After stirring for 3 hours at 20° C., the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with 1% hydrochloric acid and then water, dried with magnesium sulphate and evapoated to give the title compound as a pale yellow friable foam in essentially quantitative yield. TLC (silica)Rf 0.64 (ethyl acetate). NMR δCDCl3 2.60 (m, 3H), 3.70-4.67 (m, 2H), 5.15 (s, 2H), 5.57-5.87 (m, 2H) and 6.6-8.17 (m, 19H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([F:32])[CH:26]=1.Cl>CC(O)CCC>[ClH:2].[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[N:5][CH:4]=2)=[C:27]([F:32])[CH:26]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)cnnc2cc1OCCCN1CCCC1
Yield: 73.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (130 mg, 0.32 mmol), (prepared as described for the starting material in Example 13), and 4-chloro-2-fluoroaniline (70 mg, 0.48 mmol), in 2-pentanol (4 ml) and 5M isopropanolic hydrogen chloride (1 ml) was heated at 120° C. for 2.5 hours. The solid was filtered off, washed with isopropanol and then ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (110 mg, 66%).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[K+].C(OCC)(=O)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[CH2:25]([O:24][C:22]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 2.5 h

Procedure:
4-Piperidone hydrochloride hydrate (50.0 g, 325 mmol) and potassium bicarbonate (181.9 g, 1.82 mol) were combined in a two phase mixture of ethyl acetate (750 mL) and water (75 mL). Benzyl chloroformate (49 mL, 343 mmol) was added dropwise to the stirred mixture over 10 minutes. The mixture was stirred 2.5 hours, then it was diluted with water (700 mL) and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic phase was washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated to a light yellow oil (76.75 g, 100%). The material was found to be analytically pure and suitable for further transformation without further workup. Analysis calculated for C13H15NO3 : C, 66.94; H, 6.48; N, 6.00. Found: C, 66.67; H, 6.48; N, 5.90.
Reaction SMILES: C([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[CH2:28]([O:30][C:31]([C:33](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:34])=[O:32])[CH3:29].[CH2:54]1COCC1>>[CH2:28]([O:30][C:31](/[C:33](/[CH3:34])=[CH:54]/[C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12])=[O:32])[CH3:29]
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Product: CCOC(=O)/C(C)=C/[C@]1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
286 mg (0.75 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptan-2-carboxylate were dissolved in 12 ml of THF under argon and treated with 271 mg (0.75 mmol) of (1-ethoxycarbonylethylidene)-triphenylphosphorane. The yellow solution was stirred at 70° C. for 6 hours and subsequently concentrated. The residue remaining behind was chromatographed over silica gel (0.040-0.063 mm particle size) with ethyl acetate:hexane (9:16) as the eluent. Yield: 157 mg (45%) of pale yellow solid IR (film): 1788, 1754, 1704, 1642 cm-1MS: (M+NH4+) 483.4 1H-NMR (400MHz, CDCl3): δ[ppm]=1.32(t,3H,J=7.1 Hz),1.38(s,3H), 2.03(d,3H,J=1.5Hz), 3.05(dd,1H,J=1.8Hz, 16Hz,6-H), 3.57(dd,1 H, J=4.3Hz, 16Hz,6-H), 4.23(q,2H,J=7.1Hz), 4.89(s,1H,2-H), 5.29(dd, 1H,J=4.3, 1.8Hz,5-H), 6.94(s,1H,CHPh2), 7.20(d,1H,J=1.5Hz,=CH), 7.30-7.36(m,10H,Ph).