Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1F
Product: OC1(c2ccc(F)c(F)c2)CCC2(CC1)OCCO2
Yield: 42 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (15.6 g, 100 mmole) and 3,4-difluorophenyl magnesium bromide (100 mmole) in the usual manner. The crude product was crystallized from isopropyl ether to give the product (42%, mp: 118°-120° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[CH:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:53][CH2:52][C:47]2([O:51][CH2:50][CH2:49][O:48]2)[CH2:46][CH2:45]1)=O>>[O:51]1[C:47]2([CH2:52][CH2:53][N:44]([CH2:42][CH2:41][O:39][C:38]3[CH:37]=[CH:36][C:4]([CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]4[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=4[CH:16]4[CH2:25][CH2:24][C:23]5[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=5[CH2:17]4)=[CH:3][C:2]=3[F:1])[CH2:45][CH2:46]2)[O:48][CH2:49][CH2:50]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCC4(CC3)OCCO4)c(F)c2)C(C)C)c1
Yield: 21.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (21 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.2 mg) was obtained.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8]C=[CH:6][CH:5]=1.[C:11]([O:15]CC)(=O)[CH:12]=[CH2:13].C(OC)(=O)C=C.C(C(=C)C(OCC)=O)CC>>[CH3:3][NH2:10].[CH3:1][N:2]1[CH2:13][CH2:12][C:11](=[O:15])[CH:5]([CH2:4][CH2:9][CH3:8])[CH2:6]1
Reactant: NCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: C=C(CCC)C(=O)OCC
Agent: CN
Solvent: C=CC(=O)OC
Product: CCCC1CN(C)CCC1=O

Procedure:
In an analogous manner to the procedure described by A. Ziering et al. in J. Org. Chem. 22, 1521-1528 (1957) for the preparation of piperidin-4-ones from the corresponding acrylic acid esters by reaction with methylamine or benzylamine, reaction with ethyl acrylate or methyl acrylate, cyclization and finally decarboxylation, starting from ethyl 2-propyl-acrylate and methylamine there was obtained (3RS)-1-methyl-3-propyl-piperidin-4-one as a colourless oil; Rf : 0.38 (SiO2, methylene chloride:methanol=95:5).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][O:8][N:9]=[C:10]([C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1)[C:11]([OH:13])=O.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:7][O:8][N:9]=[C:10]([C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1)[C:11]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12)=[O:13]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(N)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Phosphorus pentachloride (3.3 g.) was added under ice-cooling to a suspension of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.5 g.) in methylene chloride (30 ml.) and the mixture was stirred for 30 minutes at ambient temperature. Methylene chloride was distilled off under reduced pressure and acetone was added to the residue to give a suspension. On the other hand, a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.2 g.) in an aqueous solution of sodium bicarbonate (0.76 g. in 50 ml. of water) was stirred for 10 minutes and acetone (50 ml.) was added thereto to give a solution. To the solution was dropwise added the above obtained suspension containing acid chloride with stirring and ice-cooling and keeping the solution at pH 7.5 to 8.5 with a 20% aqueous solution of sodium carbonate. The mixture was stirred for 1 hour at 3° to 5° C. and pH 8.0. Acetone was distilled off under reduced pressure and the residue was adjusted to pH 7.4 with a saturated aqueous solution of sodium bicarbonate and further adjusted to pH 4.5 with 10% hydrochloric acid with stirring and ice-cooling. Precipitates were filtered off and the filtrate was saturated with sodium chloride, adjusted to pH 2.5 with 10% hydrochloric acid and stirred for 1 hour. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.95 g.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22].[O-][CH2:26][CH3:27].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH2:26][CH3:27])[C:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[C:5]2[C:21]([F:23])([F:22])[F:24]
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Reactant: CC[O-]
Agent: [Na+]
Product: CCOc1nc2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1

Procedure:
The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) in place of (4-chlorophenyl)(2,4-dichloro-3-phenoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (Example 1) according to the procedure of Example 2 except only one equivalent of sodium ethoxide was used.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCN(CC)CC>CO>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][CH2:2][N:13]1[CH2:14][CH2:15][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12]1)[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)CCCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCN(CC)CCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
3-Chloro-N,N-diethylpropan-1-amine (1.6 g) is added to a mixture of tert-butyl piperazine-1-carboxylate (2.0 g) and NEt3 (1.5 ml) in methanol (30 ml). The mixture is stirred for 6 hours at 70° C. and cooled to room temperature. The solvent is removed under reduced pressure. Satd. aqueous NaHCO3 is added to the crude product and the aqueous layer is extracted with EtOAc (3×). The combined organic layers are dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give tert-butyl 4-(3-(diethylamino)propyl)piperazine-1-carboxylate (2.48 g). m/z(+) 300 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[NH:16][CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27].O>CN(C)C=O>[CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[N:16]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C=O)cnc21
Yield: 63.3 %

Procedure:
4-(Cyclohexylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (273 mg, 1.12 mmol) in N,N-dimethylformamide (3 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 61.2 mg, 1.53 mmol) for 1 hour under cooling with ice. The reaction mixture was stirred with [2-(chloromethoxy)ethyl]trimethylsilane (260 μL, 1.47 mmol) at room temperature for one day, and after addition of water, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1 (v/v)) to give the title compound as a pale yellow oil (265 mg, yield 63%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:24])[NH:12][C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([O:22][CH3:23])[C:20]=3[N:21]=2)[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:23][O:22][C:19]1[C:20]2[N:21]=[C:13]([NH:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:4]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH2:3][OH:2])[CH2:6][CH2:7]3)=[O:24])[S:14][C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: COC(=O)C(c1cccc(Cl)c1)N1CCN(C(=O)Nc2nc3c(OC)ncnc3s2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncnc2sc(NC(=O)N3CCN(C(CO)c4cccc(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3-Chloro-phenyl)-[4-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperazin-1-yl]-acetic acid methyl ester (100 mg, 0.21 mmol) in tetrahydrofuran (3 mL) at 0° C. was added lithium aluminum hydride (25 mg, 0.66 mmol). The mixture was warmed up to room temperature and stirred for two hours. LCMS analysis indicated a mixture of starting material and product. The reaction was worked up using Feiser's conditions and the crude obtained was then purified using reversed phase HPLC to give 4-[1-(3-Chloro-phenyl)-2-hydroxy-ethyl]-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide as a white powder; LRMS for C19H21ClN6O3S (M+H)+ at m/z=449. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:5]=1)([OH:3])=O.C[Li].[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([O:9][CH3:10])[C:4]([C:1]([CH:27]=[CH2:28])=[O:3])=[N:5]1
Reactant: COc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (1.09 g) in tetrahydrofuran (30 mL) was added dropwise methyl lithium (2.9 mL, 1.04 M diethylether solution) at −78° C. under nitrogen-gas atmosphere and the mixture was stirred at the same temperature for 30 minutes After warming to room temperature, to the reaction mixture was added dropwise vinylmagnesium bromide (7.7 mL, 0.97 M tetrahydrofuran solution) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water and an aqueous 1N HCl solution. After stirring, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=90/10 to 85/15) to obtain 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-vinylcarbonyl-1H-pyrazole (780 mg, yield: 70%) as a colorless solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:10]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:11]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[N:25](S(C4C=CC(C)=CC=4)(=O)=O)[CH:26]=[C:27]([CH3:28])[C:20]=23)=[C:13]([F:39])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=O)C>C(O)C>[CH2:40]([N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:11]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]3[NH:25][CH:26]=[C:27]([CH3:28])[C:20]=23)=[C:13]([F:39])[CH:12]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Nc4c(F)cc(N(Cc5ccccc5)Cc5ccccc5)cc4F)ccnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1c[nH]c2nccc(Nc3c(F)cc(N(Cc4ccccc4)Cc4ccccc4)cc3F)c12
Reaction time: 8 h

Procedure:
5 ml of a 20% strength aqueous sodium hydroxide solution are added to a solution of 390 mg (0.66 mmol) of N4,N4-dibenzyl-2,6-difluoro-N1-{3-methyl-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}benzene-1,4-diamine in 15 ml of ethanol, and the mixture is stirred overnight. The reaction solution is then poured into a mixture of water and ethyl acetate and the aqueous phase is extracted two more times with ethyl acetate. Purification by preparative HPLC affords the target compound.
Reaction SMILES: C([O-])=O.[NH4+].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH:13]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15][N:14]2C(OCC2C=CC=CC=2)=O)[CH:6]=1>CCO.[OH-].[OH-].[Pd+2]>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH:13]2[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CCc2cccnc2)C1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCNC(CCc2cccnc2)C1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
Ammonium formate (0.492 g, 7.80 mmol) was added to a mixture of 1-benzyl 4-tert-butyl 2-(2-(pyridin-3-yl)ethyl)piperazine-1,4-dicarboxylate (1.66 g, 3.90 mmol) and palladium hydroxide on carbon (˜20% Pd, 0.137 g, 0.20 mmol) in EtOH (100 mL). The reaction mixture was heated to reflux for 3 h. Upon cooling to rt, the reaction mixture was filtered though Celite®, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (0 to 5% MeOH in CH2Cl2 gradient) gave 0.683 g (60%) of the desired product. Rf=0.34 in 10% MeOH/CH2Cl2. LC-MS: RT=3.33 min., [M+H]+=292.2.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=S)[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[NH3:16]>>[NH2:16][C:7]1[CH:6]2[CH2:13][CH2:14][CH2:15][CH:5]2[C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: Fc1ccc2c(c1)C1CCCC1C(=S)N2
Reactant: N
Product: NC1=Nc2ccc(F)cc2C2CCCC12
Yield: 95 %

Procedure:
Analogously to Example 4, 8-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (240 mg, 1.08 mmol) in 7N methanolic ammonia solution (30 ml) is reacted to form 210 mg (95%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:22]1[C@H:27]([CH3:28])[CH2:26][O:25][CH2:24][C:23]1=O)=[CH:5]2>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][C@H:27]1[CH3:28])=[CH:5]2
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2N2C(=O)COC[C@H]2C)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc3ccc(Br)cc3cc2N2CCOC[C@H]2C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-4-(6-bromo-2-(4-methoxybenzylamino)quinolin-3-yl)-5-methylmorpholin-3-one (0.11 g, 0.241 mmol) in THF (5 mL) was added borane tetrahydrofuran complex, 1.0M in THF (0.482 mL, 0.482 mmol) and the resulting mixture was refluxed for 1 h. Some of the borane-amine complex was observed. The mixture was brought at RT, concentrated and dissolved in MeOH. The mixture was purged with N2 followed by the addition of Pd/C and stirred at RT for 20 min until no more complex was observed. The mixture was filtered through celite and concentrated to give (R)-6-bromo-N-(4-methoxybenzyl)-3-(3-methylmorpholino)quinolin-2-amine that was used without purification.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH3:17]>CC(C)=O>[CH2:14]([N:13]([CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1)[CH3:12])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCNC
Reactant: COC(=O)c1ccc(CBr)s1
Solvent: CC(C)=O
Product: CCCCN(C)Cc1ccc(C(=O)OC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(bromomethyl)thiophene-2-carboxylate (350 mg, 1.49 mmol) in dry acetone (6.0 mL) is added N-methylbutylamine (533 μL, 4.47 mmol) and the solution stirred at room temperature overnight. The reaction is then concentrated under reduced pressure, redissolved in methylene chloride, washed with saturated sodium bicarbonate, water, and brine. The organic layer is then dried (sodium sulfate), filtered, and concentrated under reduced pressure to yield the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 7.65 (d, J=3 Hz, 1H), 6.88 (d, J=3 Hz, 1H), 3.86 (s, 3H), 3.69 (s, 2H), 2.41-2.36 (m, 2H), 2.25 (s, 3H), 1.53-1.43 (m, 2H), 1.34-1.25 (m, 2H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=[O:11])[CH2:8][C:9]#[N:10])=[O:5])[CH3:2].[CH2:12]([O:14][CH:15](OCC)OCC)[CH3:13]>C(OC(=O)C)(=O)C>[C:9]([C:8](=[CH:15][O:14][CH2:12][CH3:13])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])#[N:10]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)NC(=O)CC#N
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)NC(=O)OCC

Procedure:
A mixture of N-ethoxycarbonylcyanoacetamide (42 g), triethylorthoformate (40 g) and acetic anhydride (100 ml) is heated at reflux for one hour. The reaction is allowed to stand until cool and then is filtered, washing with ether, to yield α-cyano-β-ethoxy-N-ethoxycarbonylacrylamide.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][OH:10]>>[CH3:9][O:10][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CO
Reactant: O=C1CCCCC1Cl
Product: COC1CCCCC1=O
Yield: 90 %

Procedure:
2-methoxycyclohexanone was prepared as in Example 4, by dissolving 98 gm. 2-chlorocyclohexanone in 750 ml. methanol and heating the solution in a sealed vessel at 160° C. for 15 minutes. The conversion was 98-99% with a yield of greater than 90%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C=O)C.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[C:3]([O:9][CH3:10])[CH:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1cc(O)ccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCC(=O)OC(C)(C)C)ccc1I
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Compound 1 (0.8 g, 3.19 mmol) was dissolved in dry DMF (30 ml). Dried potassium carbonate (1.32 g, 9.57 mmol) was added and the mixture was deaerated with argon. Tert-butyl bromoacetate (0.71 ml, 4.78 mmol) was added to the mixture and the reaction was stirred overnight at 70° C. The reaction mixture was cooled to room temperature and diluted with water (20 ml). The product was extracted with diethyl ether (3×50 ml) and dried over sodium sulphate. The product was purified by flash chromatography on silica gel using dichloromethane as an eluent. The yield was 1.1 g (96%). 1H NMR (CDCl3, 500 MHz): δ 7.66 (1H, d, J=8.5 Hz), 6.39 (1H, dd, J=8.5 Hz, 2.5 Hz), 6.34 (1H, d, J=2.5), 4.57 (2H, s), 3.79 (3H, s), 1.51 (9H, s).
Reaction SMILES: [F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:16][C:15]([NH:17][C:18](=O)OC(C)(C)C)=[N:14][N:13]=1)=[CH:7][CH:6]=2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]([F:55])([F:54])[C:33]1[CH:53]=[CH:52][C:36]([CH2:37][C@H:38]2COS(=O)(=O)[N:39]2[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[CH:35][CH:34]=1.C(OC(N[C@@H](CC1C=NC(C(F)(F)F)=CC=1)CN1N=C(C2C=C3C(=CC=2)C=NC(F)=C3)S/C/1=N\C(=O)OC(C)(C)C)=O)(C)(C)C.[Cl-].[Li+].[NH4+].[Cl-]>CN(C=O)C.CS(C)=O.O>[F:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[S:16][C:15]([NH:17][CH2:18][C@@H:38]([NH:39][C:45](=[O:46])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[CH2:37][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:55])([F:54])[F:31])=[CH:53][CH:52]=3)=[N:14][N:13]=1)=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc3cnc(F)cc3c2)s1
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Agent: CC(C)(C)OC(=O)/N=c1\sc(-c2ccc3cnc(F)cc3c2)nn1C[C@H](Cc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CNc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 12.1 %

Procedure:
tert-Butyl 5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamate (0.30 g, 0.860 mmol) and cesium carbonate (0.56 g, 1.72 mmol) in DMF (5.0 mL) were stirred under nitrogen at 55° C. for 10 minutes. tert-Butyl (4S)-4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (0.362 g, 0.946 mmol) as prepared in Schemes 1a and 1b for Example 1 was added as a solid. The resulting reaction mixture was stirred at 55° C. for 1.5 hours. The solvent was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3×140 mL), the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was partially purified by chromatography on silica gel (0-35% EtOAc:hexane) to provide the product contaminated with tert-butyl ((2Z)-3-((2S)-2-((tert-butoxycarbonyl)amino)-3-(6-(trifluoromethyl)-3-pyridinyl)propyl)-5-(3-fluoro-6-isoquinolinyl)-1,3,4-thiadiazol-2(3H)-ylidene)carbamate. The mixture was taken up in DMSO (6 mL) and water (0.019 mL). Lithium chloride (0.15 g, 3.5 mmol) was added and the mixture was heated at 100° C. with stirring 16 hours. Saturated NH4Cl was added, and the mixture was extracted with EtOAc (120 mL×3). The organic extracts were washed with water (3×100 mL), brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (0-3% MeOH-DCM) to provide the product as an off-white solid (57 mg, 30%). LCMS (API-ES) m/z: 548 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.CN.[C:19]([BH3-])#[N:20].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:20][CH3:19])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCOCC1)c1cccc(Br)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(CN1CCOCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-(4-morpholinyl)ethanone (7.8 g, 27.0 mmol) in THF (50 mL) was added methylamine (100 mL, 200 mmol, 2M solution in THF). After stirring for 15 min at room temperature, sodium cyanoborohydride (3.40 g, 54 mmol) was added followed by acetic acid (2 mL). The resultant mixture was stirred at RT for 5 days. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with 5% NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried (MgSO4) and concentrated to give [1-(3-bromophenyl)-2-(4-morpholinyl)ethyl]methylamine as yellow oil (8.10 g, 100%) which solidified after standing at room temperature. MS (ESI): 299.6 [M+H]+.