Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=O)[C:13]([C:18](=[O:24])/[CH:19]=[CH:20]/N(C)C)=[N:12]3)[C:4]=2[O:3]1.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:27]>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:20]=[CH:19][C:18](=[O:24])[C:13]([C:14]4[N:26]([C:28]5[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=5)[N:27]=[CH:16][CH:15]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc4c3OC(F)(F)O4)ccc2=O)ccn1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=410.3 (M+H)+
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:21]1[C:13]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccc(Cl)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of [(S)-1-(7-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (2.26 mmol) in DCM (5 mL) was added TFA (5 mL) and the mixture was stirred at RT for 3 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product was eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (S)-1-(7-Chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a pale orange oil (482 mg, 78%). LCMS: RT 2.11 and 2.24 min [M+H]+ 271.9
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH2:13][C@H:14]([OH:26])[CH2:15][P:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]2)(=[O:18])[O-:17])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[Li+:27]>C(O)C.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH2:13][C@H:14]([OH:26])[CH2:15][P:16]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)(=[O:17])[O-:18])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].[Li+:27]
Reactant: C[C@@H](NC[C@H](O)CP(=O)([O-])CC1CC=CCC1)c1cccc(C(=O)O)c1
Agent: [Pd]
Agent: [Li+]
Solvent: CCO
Product: C[C@@H](NC[C@H](O)CP(=O)([O-])CC1CCCCC1)c1cccc(C(=O)O)c1
Reaction time: 0.25 h

Procedure:
20 mg of 5% palladium-on-carbon are added to a solution of 0.125 g of lithium 3-{N-[1 (R)-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohex-3-enylmethyl)phosphinate in 5 ml of ethanol and the batch is hydrogenated at room temperature and normal pressure for 15 minutes. The catalyst is filtered off through Celite® and the flitrate is adjusted to a pH of 1 with ethanolic hydrochloric acid. Removal of the solvent and recrystallisation from isopropanol gives lithium 3-{N-[1 (R)-(3-carboxyphenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinate, which is identical with the compound of Example 5(f).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[CH:42]=[CH:43]/[C:44](=[NH:48])OCC)[CH:33]=[N:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>C(O)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[CH:42]=[CH:43]/[C:44]2[N:48]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[N:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Reactant: CCOC(=N)/C=C/c1cnc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/c2nc3n(n2)CCC3c2cc(F)c(F)c(F)c2)cnc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 25 h

Procedure:
A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride synthesized in Examples 253 and 254 (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 154 mg of the racemic title compound. The racemic title compound (154 mg) was purified by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) and then separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3) to obtain the title optically active compound with a retention time of 17 minutes and positive optical rotation (40 mg) and the title optically active compound with a retention time of 23 minutes and negative optical rotation (37 mg).
Reaction SMILES: [Cl:1][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:14][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4](=[O:5])[CH3:14])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cccnc1Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A solution of 2-chloro-N-methoxy-N-methyl-nicotinamide (23.6 g, 118 mmol) in tetrahydrofuran (350 mL, 0.34M) at 0° C. was treated dropwise via an addition funnel with methyl magnesium chloride (3.0M solution in tetrahydrofuran, 100 mL, 300 mmol). The reaction became a very thick opaque white mixture and was diluted with additional tetrahydrofuran (150 mL). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was carefully quenched with water (250 mL) and then partitioned between additional water (250 mL) and ethyl acetate (250 mL). The aqueous layer was back extracted with ethyl acetate (2×250 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 400 g silica gel column, 25-50% ethyl acetate/hexanes) afforded 1-(2-chloro-pyridin-3-yl)-ethanone (13.17 g, 72%) as a yellow oil.
Reaction SMILES: C1CCCCC1.[N+:7]([C:10]1[CH:23]=[CH:22][C:13]([CH2:14][O:15][C:16]([NH:18][CH2:19][CH2:20][SH:21])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[Si:24]([O:31][C@@H:32]([C@H:34]1[C:62](=[O:63])[N:36]2[C:37]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:38](S(C3C=CC=CC=3)=O)[C@H:39]([CH3:40])[C@H:35]12)[CH3:33])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1>[Si:24]([O:31][C@@H:32]([C@H:34]1[C:62](=[O:63])[N:36]2[C:37]([C:49]([O:51][CH2:52][C:53]3[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=3)=[O:50])=[C:38]([S:21][CH2:20][CH2:19][NH:18][C:16]([O:15][CH2:14][C:13]3[CH:22]=[CH:23][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=3)=[O:17])[C@H:39]([CH3:40])[C@H:35]12)[CH3:33])([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:26])[CH3:25]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S(=O)c3ccccc3)[C@H](C)[C@H]12
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
0.14 ml (0.21 mmol) of a cyclohexane solution containing 1.5M of a lithiumdiisopropylamide-tetrahydrofuran complex was added to 2 ml of an ice-cooled tetrahydrofuran suspension containing 91 mg (0.352 mmol) of a magnesium bromide-diethyl ether complex, and the resulting mixture was stirred for 10 minutes an this temperature. At the end of this time, 2 ml of a tetrahydrofuran solution containing 55 mg (0.207 mmol) of 2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan were added to the mixture, which was then stirred for a further 10 minutes in an ice bath. 102 mg (0.174 mmol) of the S-oxide isomer of lower polarity of the 4-nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 2) were then added to the mixture, and the mixture was stirred for a further 15 minutes. At the end of this time, a saturated aqueous solution of ammonium chloride was added, and then the mixture was extracted with ethyl acetate. The resulting organic extract was washed first with water and then with a saturated aqueous solution of sodium chloride, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 15 g of silica gel, using a 1:19 by volume mixture of ethyl acetate and hexane as the eluent, to give 104 mg (yield 84%) of the title compound as a foam-like solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:23](=[O:24])[C:11]2[CH:12]=[N:13][C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:23](=[O:24])[C:11]2[CH:12]=[N:13][C:14]3[C:15]([N+:20]([O-:22])=[O:21])=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]=2[N:9]1[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1[nH]c2c(cnc3c([N+](=O)[O-])cccc32)c1=O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(cnc3c([N+](=O)[O-])cccc32)c(=O)n1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
To a mixture of 2-tert-butoxycarbonyl-2,3-dihydro-6-nitro-1H-pyrazolo[4,3-c]quinolin-3-one (450 mg) and potassium carbonate (565 mg) in dimethylformamide was added methyl iodide (580 mg), and the mixture was stirred for 2 hours at 60° C. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane-ethyl acetate) to give 2-tert-butoxycarbonyl-2,3-dihydro-1-methyl-6-nitro-1H-pyrazolo[4,3-c]quinolin-3-one (114 mg).
Reaction SMILES: [Mg].[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.[CH3:14][C:15]([CH3:19])=[CH:16][CH2:17]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH3:2][O:3][CH:4]([O:12][CH3:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:17][CH:16]=[C:15]([CH3:19])[CH3:14])[CH:6]=1
Reactant: CC(C)=CCBr
Reactant: COC(OC)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(OC)c1cccc(CC=C(C)C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Magnesium metal (1.2 g) was added to 2 ml of tetrahydrofuran. With stirring at room temperature, 20 ml of a solution of 2.0 g of 3-bromobenzaldehyde dimethyl acetal in a 1:1 mixture of tetrahydrofuran and ethyl ether was added dropwise over the course of 1 hour. With stirring under ice cooling, 15 ml of a tetrahydrofuran solution of 2.25 g of 3-methyl-2-butenyl bromide was added to the resulting solution. The temperature of the mixture was returned to room temperature, and then it was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture to terminate the reaction. Ethyl ether was added, and the reaction mixture was treated in a customary manner to give 1.71 g (yield 90%) of 3-(3-methyl-2-butenyl)benzaldehyde dimethyl acetal as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[CH:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[CH:28]=3)[CH:17]=2)[CH:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1cc2ccc(Br)cc2c(OCc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(-c2ccc3cc(Cl)nc(OCc4ccccc4)c3c2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of 1-(benzyloxy)-7-bromo-3-chloroisoquinoline (1.00 g, 2.86 mmol, 1.0 eq), 3-methoxyphenylboronic acid (435 mg, 2.86 mmol, 1.0 eq), K2CO3 (2.13 g, 15.4 mmol, 5.4 eq) in dioxane (10 mL) and H2O (5 mL) was added Pd(PPh3)2Cl2 (100 mg, 0.15 mmol, 0.05 eq) under N2 atmosphere. The resulting mixture was stirred at 110° C. under N2 atmosphere overnight. The solvent was removed in vacuo and the residue was purified with chromatography on silica gel (hexane/ethyl acetate 250:1) to give 550 mg of lxvi-a as white solid (yield 37%). LCMS m/z=376.0 (M+1) (Method B) (retention time=2.43 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:24]#[N:25])[C:7]=1[C:8]1[CH:13]=[C:12](B2OC(C)(C)C(C)(C)O2)[CH:11]=[CH:10][C:9]=1[F:23].Br[C:27]1[N:31]2[N:32]=[CH:33][C:34]([C:36]([OH:39])([CH3:38])[CH3:37])=[N:35][C:30]2=[N:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:24]#[N:25])[C:7]=1[C:8]1[CH:13]=[C:12]([C:27]2[N:31]3[N:32]=[CH:33][C:34]([C:36]([OH:39])([CH3:37])[CH3:38])=[N:35][C:30]3=[N:29][CH:28]=2)[CH:11]=[CH:10][C:9]=1[F:23]
Reactant: CC1(C)OB(c2ccc(F)c(-c3c(F)cccc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: CC(C)(O)c1cnn2c(-c3ccc(F)c(-c4c(F)cccc4C#N)c3)cnc2n1

Procedure:
6,2′-Difluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-2-carbonitrile was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol in 32% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 206° C.; 1H NMR (360 MHz, CDCl3) δ1.71 (6H, s), 3.28 (1H, br s), 7.37-7.66 (4H, m), 8.15 (2H, m), 8.26 (1H, s), 8.78 (1H, s); MS (ES+) mn/z 392 [M+H]+. Anal. Found: C, 64.66; H, 3.93, N, 17.71%. Required for C21H15F2N5O: C, 64.45; H, 3.86; N, 17.89%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:12]\[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[N+:20]([O-])=O)/[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1>C(O)(=O)C.O.C(OCC)(=O)C.[Fe]>[NH2:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1/[CH:12]=[C:8](\[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)/[C:9]([OH:11])=[O:10]
Reactant: O=C(O)/C(=C/c1ccc(Cl)cc1[N+](=O)[O-])c1ccc(Br)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Cl)ccc1/C=C(/C(=O)O)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
To a 50° C. solution of 135 g of (2E)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid from Step 1 in 1.2 L of acetic acid and 80 mL of water, was added 98 g of iron (powder) portion wise maintaining the temperature below 50° C. The mixture was stirred 2 hrs at 50° C., cooled down to room temperature, diluted with ethyl acetate (1 L) and filtered through a plug of celite. Water (1 L) was added, the layers were separated and the organic layer washed 2 times with water, brine, dried over magnesium sulphate and volatiles were removed under reduced pressure. Residual acetic acid was removed by the addition of 1 L of H2O to the crude mixture, the solution was filtered and washed with an additional 1 L of H2O and finally the solid was dried under high vacuum to afford 130 g of (2E)-3-(2-amino-4-chlorophenyl)-2-(4-bromophenyl)acrylic acid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH2:22][C:23]([C:25]3[C:26]([C:32]([O:34]C)=O)=[C:27]([CH3:31])[NH:28][C:29]=3[CH3:30])=O)[CH:18]=[CH:19][C:20]=2[F:21])=[O:14])[CH2:9][CH2:8]1)[CH3:5]>C(O)(=O)C>[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[F:21])[CH2:22][C:23]2[C:25]3[C:26](=[C:27]([CH3:31])[NH:28][C:29]=3[CH3:30])[C:32](=[O:34])[NH:2][N:3]=2)=[O:14])[CH2:9][CH2:8]1)[CH3:5]
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C)[nH]c(C)c3C(=O)OC)ccc2F)CC1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)[nH]c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.4 %

Procedure:
Hydrazine hydrate (0.037 mL, 0.49 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (53) (0.200 g, 0.45 mmol) in acetic acid (8 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford a crude gum, which was triturated with a mixture of NMP, DMSO and water to give a solid which was collected by filtration, washed with ether and dried under vacuum to give the desired compound as a white solid (0.112 g, 58.4% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.29 (1H, m), 1.42 (1H, m), 1.71 (1H, m), 1.86 (1H, m), 2.27 (3H, s), 2.51 (3H, s), 3.04 (1H, m), 3.24-3.39 (2H, m), 3.46 (2H, m), 3.52 (1H, m), 3.97 (1H, s), 4.07 (2H, s), 7.13-7.30 (3H, m), 11.07 (1H, s), 11.94 (1H, s); m/z (LC-MS, ESI+), RT=1.62 min (M+H=427.12).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.O[Li].O.Cl>C1COCC1.O>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:4]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]([OH:22])=[O:2])=[CH:12][CH:11]=1
Reactant: COC(=O)C(COc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COc1ccc(Br)cc1)C(=O)O
Reaction time: 6 h
Yield: 78 %

Procedure:
To a solution of the compound obtained in step d above (22d) (1.087 g, 2.91 mmoL) in THF (40 mL) at 0° C. was added a solution of LiOH H2O (244 mg, 5.82 mmol) in water (10 mL). After being stirred for 6 h, 0.5 N HCl (5 mL) was added and the reaction was concentrated under vacuum. The residue was diluted with EtOAc and washed with brine. The combined organic layers were dried over Na2SO4 and concentrated; the residue was purified by silica gel column chromatography to give the title compound as a colourless oil (816 mg, 78% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[OH-].[NH4+].[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CC=CC1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)NCC1=C(CC(=O)O)CCCC1

Procedure:
A solution of α-[2-(t-butoxycarbonylaminomethyl)-1,4-cyclohexadienyl]-acetic acid (1.33 g., 5 mmoles) in 3% ammonium hydroxide (10 ml.) was hydrogenated at 40 psi with palladium on charcoal (10%, 0.2 g.). A theoretical amount of hydrogen was taken up in 3 hours. The catalyst was removed and the filtrate was acidified to pH 2 with dil. HCl and extracted with ethyl acetate (2×50 ml.). The combined extracts were washed with water (20 ml.), dried with Na2SO4 and evaporated under reduced pressure to afford an oil (1.34 g.) which solidified on standing for several days. Recrystallization from n-hexane - ethyl acetate gave 1.2 g. title product as colorless prisms melting at 118°-119° C.
Reaction SMILES: C[Si]([PH:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O-:9])[O:6][CH2:7][CH3:8])(C)C.[CH:17]([C:19]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:20])=[CH2:18].C(Cl)(Cl)Cl>O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]([CH2:17][CH2:18][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])=[O:20])=[CH:26][CH:25]=1
Reactant: CCOC(OCC)[PH]([O-])(OCC)[Si](C)(C)C
Reactant: C=CC(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(OCC)P(=O)(CCC(=O)c1ccc(Cl)cc1)OCC
Reaction time: 1 h

Procedure:
17.7 g of ethyl trimethylsilyl(diethoxymethyl)phosphonite is added dropwise to a stirred solution of 11.7 g of 4-chlorophenyl vinyl ketone under an atmosphere of nitrogen, at room temperature. The reaction mixture is stirred for a period of 1 hour, 25 ml of chloroform is added followed by 10 ml of water and this mixture is vigorously stirred for a period of 0.5 h. The organic layer is then separated, dried over magnesium sulphate and concentrated under reduced pressure to give ethyl 2-4-chlorobenzoyl-ethyl(diethoxymethyl)phosphinate as an oil, 31P=+45.5 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[CH:14](N)=[O:15].N>C(O)=O.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][CH:14]=[O:15])=[N:4][C:3]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1nc(-c2cccnc2)c(Cl)s1
Reactant: NC=O
Agent: N
Solvent: O
Solvent: O=CO
Product: O=CNc1nc(-c2cccnc2)c(Cl)s1

Procedure:
5-Chloro-4-(pyridin-3-yl)-thiazol-2-amine (20 g) was dissolved in formic acid (40 ml) and formamide (20 ml) and the mixture was heated at 90° C. for six hours. After cooling, the mixture was diluted with water (240 ml) and basified with aqueous ammonia solution. The resulting solid was isolated by filtration, and dried in vacuo at 60° C. to give N-[5-chloro-4-(pyridin-3-yl)-thiazol-2-yl]-formamide, (22,8 g) Mp 229° C.
Reaction SMILES: Cl[C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1.[CH2:26]([NH2:28])[CH3:27].Cl>CC(N(C)C)=O>[CH2:26]([NH:28][C:2]1[S:10][C:9]2[C:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])=[N:7][C:6]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:5][C:4]=2[CH:3]=1)[CH3:27]
Reactant: CCN
Reactant: O=C(c1cccs1)c1nc(NCc2cccnc2)nc2cc(Cl)sc12
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCNc1cc2nc(NCc3cccnc3)nc(C(=O)c3cccs3)c2s1
Temperature: 170 °C
Yield: 40 %

Procedure:
A stirred solution of Example 5 (0.025 g, 0.065 mmol) in dimethyl acetamide (1.5 ml) was treated with ethylamine (2.0M in THF, 0.65 mmol). The solution was heated to 170° C. for 30 min in a microwave reactor. The cooled solution was poured on to aqueous HCl solution (2.5M, 25 ml). The aqueous solution was washed with ethylacetate (50 ml) and basified (pH 9) using aqueous sodium hydroxide solution (5M). The title compound was filtered as an orange solid in 40% yield, >90% purity. LC-MS m/z=396.0 [M+H]+; RT=2.78; LC-MS method 1. 1H NMR: δH (400 MHz, D6-DMSO) 1.21 (3H, t, J 7.0 Hz), 3.22-3.33 (2H, m), 4.68 (2H, bd), 5.82 (1H, s), 7.23-8.63 (11H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:24]#[N:25])[C:5](F)=[C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)[CH:7]=1.O.[NH2:27][NH2:28]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([C:24]#[N:25])[CH:3]=1)[NH:28][N:27]=[C:8]2[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)cc(C#N)c2F)CC1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2n[nH]c3c(C#N)cc(Br)cc23)CC1
Yield: 58.3 %

Procedure:
A mixture of 1,1-dimethylethyl 4-[(5-bromo-3-cyano-2-fluorophenyl)carbonyl]-1-piperidinecarboxylate (1.35 g, 3.3 mmols) and hydrazine hydrate (0.21 ml, 6.9 mmols) in ethanol (30 mL) was heated at reflux overnight. After cooling, the solvent was evaporated and the residue was purified by flash chromatography eluting with pentane/ethyl acetate 4:1 v/v to give the title compound (0.78 g) as a yellow solid (59%).