Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][OH:2].NC1C=CN=CC=1.[CH2:10]([C@H:12]1[O:14][CH2:13]1)[Cl:11].[C]=O.[C:17]([OH:21])(C)(C)C>>[CH3:1][O:2][C:17](=[O:21])[CH2:13][C@H:12]([OH:14])[CH2:10][Cl:11]
Reactant: CC(C)(C)O
Reactant: CO
Reactant: ClC[C@@H]1CO1
Agent: Nc1ccncc1
Agent: [C]=O
Product: COC(=O)C[C@H](O)CCl
Temperature: 25 °C
Yield: 92 %

Procedure:
In a 50 mL-volumetric autoclave were added deaerated methanol (5 mL) and t-butanol (3 mL), and thereto were added 4-aminopyridine (47 mg, 0.5 mmol) and (S)-epichlorohydrin (1.9 g, 20 mmol, >99% ee). Then to the mixture was added crystalline dicobaltoctacarbonyl complex (171 mg, 0.5 mmol). After covering the autoclave with a cap, carbon monoxide (1 MPa) was introduced therein and the mixture was reacted at 40° C. for 5 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to Kugelrohr distillation to give (S)-4-chloro-3-hydroxybutanoic acid methyl ester (2.8 g, 92%, >99% ee) as a colorless oil.
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][OH:6].[C:8]1([C:14]([C:28]2[CH:33]=[CH:32][C:31](F)=[CH:30][CH:29]=2)=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][O:6][C:31]1[CH:30]=[CH:29][C:28]([C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:16]([F:19])([F:18])[F:17])=[CH:33][CH:32]=1
Reactant: COc1ccc(C(=C(c2ccccc2)c2ccc(F)cc2)C(F)(F)F)cc1
Reactant: CN(C)CCO
Agent: [Na]
Solvent: CCOCC
Product: COc1ccc(C(=C(c2ccccc2)c2ccc(OCCN(C)C)cc2)C(F)(F)F)cc1
Yield: 90.3 %

Procedure:
0.39 g (0,017 g.-atoms) of sodium are dissolved in 3.12 g (35 mmoles) of 2-dimethylamino-ethanol. 3.15 g (8.5 mmoles) of 1-phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propene are added to the solution, and the mixture is heated at 150°-155° C. for one hour. The reaction mixture is cooled, diluted with 200 ml of ether, washed with water until neutral, dried and evaporated. The residue is dissolved in 30 ml of hexane, the solution is filtered, and the filtrate is evaporated. 3.39 g (90%) of 1-[4-(2-dimethylamino-ethoxy)-phenyl]-1-phenyl-3,3,3-trifluoro-2-(4-methoxyphenyl)-propene are obtained as a resinous substance; the product is a 3:4 mixture of the (Z) and (E) isomers.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[Br:23][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: CC(Br)c1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 85.4 %

Procedure:
19 g of 4'-ethyl-4-benzoyl-biphenyl, 12.4 g of N-bromosuccinimide and 0.12 g of azaisobutyronitrile in 400 mL of carbon tetrachloride were heated to boiling under reflux for 1.5 hours. After filtering off the precipitated material the solution was evaporated and the residue was recrystallized from cyclohexane. There were obtained 20.7 g (85%) of 4'-(1-bromo-ethyl)-4-benzoylbiphenyl as a colorless solid with a m.p. of 132°-134° C.
Reaction SMILES: [OH:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:1][C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]2[S:6][C:7]([C:9]#[N:10])=[CH:8][C:4]=2[CH:3]=1
Reactant: COc1cc2sc(C#N)cc2cc1O
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2sc(C#N)cc2cc1OC(F)F
Temperature: 40 °C

Procedure:
A mixture of 5-hydroxy-6-methoxy-benzo[b]thiophene-2-carbonitrile (10.30 g) and anhydrous potassium carbonate (7.63 g) was treated with a solution of dry dimethylformamide (110 ml) which has been previously saturated with chlorodifluoromethane gas. The mixture was then sealed in an autoclave, stirred, and heated to 40° C. After 3 days the reaction mixture was cooled and poured into water (700 ml). The resultant precipitate was iiltered off, dried, and extracted with hot dichloromethane (300 ml). The organic extract was concentrated then poured through a column of fine silica (200 g). The appropiate fractions were combined and evaporated to dryness to give 5-difluoromethyloxy-6-methoxy-benzo[b]thiophene-2-carbonitrile as an off-white solid (5.49 g), m.p. 99°-101° C.
Reaction SMILES: [O:1]([C:3](C)(C)C)[K].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC)=O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:29])[CH:21]([CH:3]=[O:1])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)O[K]
Reactant: O=C(CCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Solvent: COC=O
Solvent: C1CCOC1
Product: O=CC(Cc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Yield: 130.8 %

Procedure:
Into a 100 mL 3-neck round-bottom flask was weighed 0.336 g KO-t-Bu and 4 mL anhydrous THF was added. The mixture was cooled with an ice bath under nitrogen, and to it was added a solution of 0.29 g 1-(1-benzylpiperidin-4-yl)-3-phenyl-1-propanone from the last step and 1.80 g methyl formate in 12 mL THF over 5 minute with stirring. After stirring for an additional 15 min, the cooling bath was removed, and the yellowish cloudy mixture was stirred for 2 hours. The mixture was then poured into water, extracted with 4×50 mL ether, 40 mL dichloromethane, and 3×40 mL THF and the combined organic layers were washed with 50 mL each of water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.414 g of the title compound as a sticky yellowish solid. This crude product was used without further purification in the next step. RF: 0.59 (EtOAc with 3% (v/v) Et3N and 5% (v/v) MeOH). 1H NMR (500 MHz, DMSO-d6): δ7.97 (s, 1H), 7.20˜7.30 (m, 5H), 7.14˜7.17 (m, 2H), 7.04˜7.09 (m, 3H), 6.85 (s, 1H), 3.45 (s, ˜2H), 2.81˜2.89 (m, 1H), 2.76˜2.80 (m, 2H), 1.97˜2.03 (m, 2H), 1.46˜1.56 (m, 4H). The Ph—CH2—C═ signal was not observed, possibly overlapping with the large water signal. ESI-MS 336.1 (M+H), HPLC A: 2.32 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[C:16]2C(=[CH:12][CH:13]=[CH:14][CH:15]=2)N[C:9]=1[CH3:17].[OH-:18].[Na+].[CH3:20][C:21]([N:23]([CH3:25])C)=O>O>[CH3:6][O:7][C:8]1[CH:16]=[C:15]2[C:25](=[CH:17][CH:9]=1)[NH:23][C:21]([CH3:20])=[C:14]2[C:13](=[O:18])[CH3:12]
Reactant: COc1c(C)[nH]c2ccccc12
Reactant: [OH-]
Reactant: CC(=O)N(C)C
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2[nH]c(C)c(C(C)=O)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
Dimethylacetamide (17.5 ml, 188.4 mmol) is added dropwise with stirring to phosphorous oxychloride (12.9 ml, 138.2 mmol) at 0° C. Stirring is maintained for 45 minutes, at which time the bath is removed and -methoxy-2-methylindole (20.25 g, 125.6 mmol) in 15 ml of dimethylacetamide is added dropwise over a period of 75 minutes. The resulting mixture is warmed to 40°-45° C. for 4 hours. The reaction mixture is cooled to 0° C, and 100 g of ice water is added followed by dropwise addition of a solution of sodium hydroxide (50 g) in water (75 ml). The first 1/3 of this sodium hydroxide solution is added slowly and the remainder is added quickly. The exothermic reaction is quickly warmed to boiling for 15 minutes, cooled to room temperature and refrigerated overnight. The resulting crystals are collected by filtration and rinsed four times with water. Recrystallization from ethanol/water gives 17.2 g (67.2%) of pure 1-(5-methoxy-2-methyl-1H-indol-3- yl)ethanone; mp 229.0°-230.5° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[O:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[C:40](B(O)O)[C:35]=2[O:34][CH2:33][CH2:32]1>>[O:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)[NH:20][C:19]4=[O:29])[C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1cccc2c1OCCO2
Product: O=C(O)c1cnn(-c2nc3ccc(-c4cccc5c4OCCO5)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 1,4-benzodioxan-5-boronic acid in step C. MS (ESI): mass calcd. for C20H14N4O5, 390.1; m/z found, 391.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.00 (s, 1H), 12.87 (s, 1H), 8.97 (s, 1H), 8.25 (s, 2H), 8.10 (d, J=7.8 Hz, 1H), 7.73 (s, 1H), 7.28-7.24 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 4.30 (s, 4H).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:43]([O:47][C:48](=[O:57])[C@H:49]([CH2:51][O:52]C(C)(C)C)[NH2:50])([CH3:46])([CH3:45])[CH3:44]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][C@H:49]([C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:57])[CH2:51][OH:52])=[O:36])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)N[C@@H](CO)C(=O)OC(C)(C)C)cc2)cc1

Procedure:
The product from Example 233 and O-tert-butyl L-serine tert-butyl ester hydrochloride were processed as described in Example 251A to provide the titled compound.
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.O1CCCC1.[Br:10][C:11]1[N:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[H-].[Na+]>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:1][O:2][CH3:3])=[CH:15][N:16]=1
Reactant: Oc1ccc(Br)nc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Br)nc1

Procedure:
Methoxymethyl chloride (73 ml) was added to a tetrahydrofuran (1.3 L) solution of 6-bromo-3-pyridinol (129 g) thus obtained, and sodium hydride (40% liquid paraffin added, 32 g) was added to it in such a manner that the inner temperature could not be above −10° C. Water was added, and extracted with ethyl acetate, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and this was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=9/1 to 8/1) to obtain the entitled compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[CH2:55][C:56]([NH2:58])=[O:57]>O>[C:56]([CH2:55][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)(=[O:57])[NH2:58]
Reactant: NC(=O)CCl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OCC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 56.8 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol) and cesium carbonate (63.4 mg, 195 μmol) were combined with dimethyl formamide (2 mL). 2-Chloroacetamide (15.2 mg, 162 μmol) was added to the mixture with stirring to give a white suspension. The tube was capped and heated at 50° C. overnight. The reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with ethyl acetate in hexanes) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid carbamoylmethyl ester as an off-white solid (62 mg, 58% yield). LCMS (ES+) m/z calcd. for C33H33Cl2F2N4O5 [(M+H)+]: 673. found: 673.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC.C(OCC)(=O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C1CCCN1c1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCN1c1ccc(OCc2cccc(F)c2)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
A mixture of 2.73 g (15.4 mmol) of 1-(4-hydroxy-phenyl)-pyrrolidin-2-one, 3.2 g (16.9 mmol) of 3-fluorobenzylbromide and 4.26 g (31 mmol) of potassium carbonate in 100 ml of 2-butanone is heated at 80° C. for 18 hours. After cooling to RT, the reaction mixture is treated with water and ethyl acetate. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure. The solid residue is crystallised from ether to yield 3.86 g (88% of theory) of 1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one as a colorless solid. MS: m/e=286.0 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:24])[C:16](=[O:23])N2CCSC2=S)[NH:13][C:12]1=[O:25])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:26]([O:29][C:30]([N:32]1[CH2:36][CH:35]([SH:37])[CH2:34][CH:33]1[CH2:38][O:39][CH2:40][CH2:41][F:42])=[O:31])[CH:27]=[CH2:28].C(N(CC)CC)C.C(O)(=O)C>O1CCCC1>[CH2:26]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([S:37][C:16](=[O:23])[C@@H:15]([C@H:14]2[NH:13][C:12](=[O:25])[C@@H:11]2[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])[CH3:24])[CH2:34][C@H:33]1[CH2:38][O:39][CH2:40][CH2:41][F:42])=[O:31])[CH:27]=[CH2:28]
Reactant: C=CCOC(=O)N1CC(S)CC1COCCF
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)N1CCSC1=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)[C@H](C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C[C@H]1COCCF
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 42.3 %

Procedure:
To a solution of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]- 4-{(1R)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (3.17 g) in tetrahydrofuran (30 ml) were added 1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)-4-mercaptopyrrolidine (2.21 g) and triethylamine (1.46 ml) at 5° C., and the mixture was stirred at room temperature for 8.5 hours. Acetic acid (0.63 ml) was added to the mixture and the mixture was evaporated. The residue was dissolved in water and ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The residue was purified by chromatography on silica gel eluting with a mixture of dichloromethane and ethyl acetate (2:1 V/V) to give (3S,4S)-4-[(1R)-2-{(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethyloxymethyl)pyrrolidin-4-yl-thio}-1-methyl-2-oxoethyl]-3-{(1R)-1-(t-butyldimethylsilyl-oxy)ethyl}-2-azetidinone (1.82 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:26]1[C:31]([CH2:32][CH3:33])=[CH:30][N:29]=[CH:28][N:27]=1.Cl.C[O-].[Na+].CO>C(O)C>[CH2:32]([C:31]1[C:26]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:24][CH:23]=2)=[N:27][CH:28]=[N:29][CH:30]=1)[CH3:33]
Reactant: Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Reactant: CCc1cncnc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CCc1cncnc1Nc1ccc(C(=O)CCC2CCN(Cc3ccccc3)CC2)cc1
Yield: 58.9 %

Procedure:
To 10 ml of ethanol were added 0.23 g of 4-[3-(1-benzylpiperidin-4-yl)propanoyl]aniline and 0.13 g of 4-chloro-5-ethylpyrimidine, and after adding 2 ml of an ethanol solution of hydrochloric acid (containing 0.071 g of hydrochloric acid), the mixture was reacted under reflux for 2 hours. After cooling, a 28% sodium methylate-methanol solution was added to the reaction mixture to make it alkaline, and then the mixture was condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography to obtain 0.18 g of the title compound as pale yellow crystal.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].CS(O[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=O)=O>CN1C(=O)CCC1.O.CO>[CH2:28]([O:4][CH2:3][CH2:2][CH2:1][OH:5])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: OCCCO
Reactant: CCCCCCCCCCCCCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOCCCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Under an inert atmosphere, e.g., nitrogen, a reactor was charged with 1,3-propanediol (4.07 kg) and NMP (30 L). The reaction was cooled to −5 to 5° C. and kept under a nitrogen atmosphere. Sodium hydride (1.07 kg, 60% in mineral oil) was cautiously added portion-wise. After the addition was complete, the reaction was stirred at room temperature for an additional 2 hours. A solution of hexadecyl methanesulfonate 4 (4.39 kg) dissolved in NMP (10 L) was added slowly to the reaction mixture at 20 to 55° C. The resulting solution was stirred for 12 to 28 hours at 20 to 35° C. The reaction was monitored by GC-MS and was considered complete when the conversion rate was ≧95%. The reaction mixture was cooled down to −5 to 5° C. and slowly diluted with water (15 L). The reaction was extracted with ethyl acetate (2×25 L). The organic phase was washed with water (20 L), dried over Na2SO4 and concentrated to give a brown oil. The crude product was dissolved in methanol (20 L) and aged at 20 to 30° C. for 12 hours. The resulting solid impurities were filtered and discarded and the filtrate was concentrated. Acetonitrile (40 L) was added to the concentrate and the mixture was aged 5 to 15° C. for 16 hours. The solid was filtered and dried at 25 to 30° C. to afford 5 as a white solid (3.1 kg, 77%). Typical HPLC (AUC) purity was >95%. 1H-NMR was consistent with structure.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1C(=O)CCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1cc(C)nc(Nc2cc(Cl)nnc2C(N)=O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Temperature: 130 °C
Yield: 19.6 %

Procedure:
To a solution of 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (140 mg, 504 μmol) in NMP (2.52 mL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (216 mg, 1.01 mmol) and the mixture heated at 130° C. for 72 h. The reaction mixture was cooled and diluted with ethyl acetate and brine. The organic phase was washed with brine (2×) and water (1×), then the organic phase was concentrated in vacuo then purified by chromatography (silica, 40-100% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(4,6-dimethylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (75 mg, 98.8 μmol, 20%) as an orange solid. MS (EI/CI) m/z: 456.2 [M+H].
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1[F:18])\[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC[CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(O)C.C(OCC)C>[F:18][C:12]1[CH:13]=[CH:14][C:15]([I:17])=[CH:16][C:11]=1[C:10]([C:4](=[CH:3][NH:2][CH2:20][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:19]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: NCCN1CCOCC1
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=CNCCN1CCOCC1)C(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
A suspension of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (WO2006/010733, 294 mg, 0.75 mmol) in ethanol (2.500 mL) and diethyl ether (5 mL) was cooled 0° C. and 4-(2-aminoethyl)morpholine (103 mg, 0.79 mmol) was added dropwise. The reaction mixture was stirred for 3 h, then concentrated under reduced pressure to give the desired product (358 mg). MS (ESP): 477 (M+H+) for C18H22FIN2O4.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][CH2:16][CH2:15][C:14]4[N:10]([N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[CH:13]=4)[C:9]=3[CH:26]=2)[CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH:23]([N:19]1[C:18]([C:12]2[CH:13]=[C:14]3[N:10]([C:9]4[CH:26]=[C:5]([CH:3]5[CH2:2][N:1]([C:27](=[O:29])[CH3:28])[CH2:4]5)[CH:6]=[CH:7][C:8]=4[O:17][CH2:16][CH2:15]3)[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CNC3)ccc1OCC2
Product: CC(=O)N1CC(c2ccc3c(c2)-n2nc(-c4ncnn4C(C)C)cc2CCO3)C1

Procedure:
Following the procedure for 148, 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene was reacted with acetic anhydride to give 149 as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1 H); 7.85 (d, J=2.17 Hz, 1 H); 7.27-7.20 (m, 1 H); 7.19 (d, J=8.32 Hz, 1 H); 6.85 (s, 1 H); 5.68-5.59 (m, 1 H); 4.59-4.50 (m, 3 H); 4.44 (t, J=9.38 Hz, 1 H); 4.18-4.11 (m, 1 H); 4.13-4.05 (m, 1 H); 3.89-3.80 (m, 1 H); 3.16 (t, J=5.93 Hz, 2 H); 1.91 (s, 3 H); 1.57 (d, J=6.62 Hz, 6 H). LCMS: RT=9.50 min, M+H+=393