Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[Li+]>ClCCl>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)/C=C/c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C

Procedure:
In accordance with the method of “Helvetica Chimica Acta”, 2002, vol. 85, no. 11, p. 3616-3623, triethylamine was added under ice-cooling to a mixture of trans-cinnamic acid chloride, (S)-4-benzyl-2-oxazolidinone, lithium chloride and dichloromethane, and then stirred at room temperature for 3Hours. Thereafter, (4S)-4-benzyl-3-[(2E)-3-phenylprop-2-enoyl]-1,3-oxazolidin-2-one was obtained by purifying it in the standard method. FP: 308.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([CH3:26])[CH:31]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)on1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3)c2cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(3-methylisoxazol-5-yl)carbamate (81 mg) were added to toluene (5 ml), then diisopropylethylamine (0.88 ml) was added and the mixture was heated and stirred at 100° C. for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate:toluene (1:1) mixed solvent to obtain the title compound (102 mg).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].Cl[C:6]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>CO>[CH3:1][O:2][C:6]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1OC

Procedure:
A sodium methoxide solution prepared from 3.46 g (0.15 mole) of sodium and 150 ml of absolute methanol is added dropwise at 40° C in the course of 1 hour to a solution of 312 g (0.15 mole) of methyl 2,6-dichloronicotinate in 100 ml of methanol. The reaction mixture is refluxed for 3 hours and the solvent is then evaporated in vacuo. The dry residue is triturated with methylene chloride, the undissolved constituents are filtered off and the filtrate is evaporated in vacuo to dryness. The crystallised residue is recrystallised from petroleum ether to yield pure methyl 2-methoxy-6-chloronicotinate with a melting point of 68°-69° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([C@@H:10]1[CH2:14][C:13](=[N:15][O:16][CH3:17])[CH2:12][N:11]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][CH:21]=1)=[O:19])=[O:9])(=O)C.[OH-].[Na+].CO>C1COCC1>[C:23]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][C:20]([C:18]([N:11]2[CH2:12][C:13](=[N:15][O:16][CH3:17])[CH2:14][C@H:10]2[C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9])=[O:19])=[CH:25][CH:24]=1
Reactant: CON=C1C[C@@H](C(=O)NCCOC(C)=O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CON=C1C[C@@H](C(=O)NCCO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.4 %

Procedure:
A solution was made containing the side-chain protected compound from the previous step, e.g. 2-({[(2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)pyrrolidinyl]carbonyl}amino)ethyl acetate (450 mg, 10.6 mmol) in THF (10 ml). An aqueous solution (10 ml) of sodium hydroxide (75 mg, 19 mmol) with methanol (5 ml) was added and the reaction stirred at room temperature for three hours. The solvent was removed in vacuo and the crude purified by column chromatography using THF (100%) to give the expected final product, e.g. (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N-(2-hydroxyethyl)-4-(methoxyimino)-2-pyrrolidinecarboxamide (300 mg, 75%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:16][CH:17]2[CH2:19][CH2:18]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCC2CC2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a solution of 6-bromopyridin-3-ol (5.00 g, 28.8 mmol) in DMF (50 mL) were added potassium carbonate (7.96 g, 55.6 mmol) and (bromomethyl)cyclopropane (4.18 mL, 43.1 mmol), and the mixture was stirred at 60° C. for 30 min. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to 1:1) to give the title compound (6.32 g, yield 96%) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[S:21][C:22]([CH2:25][NH:26][CH2:27][CH3:28])=[CH:23][N:24]=1.O>CN(C)C=O>[CH3:12][O:11][C:4]1[N:3]=[C:2]([N:26]([CH2:25][C:22]2[S:21][C:20]([Cl:19])=[N:24][CH:23]=2)[CH2:27][CH3:28])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: CCNCc1cnc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cnc(Cl)s1)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 57.8 %

Procedure:
1.26 g 2-chloro-6-methoxy-3-nitropyridine and 10 mL N,N-dimethylformamide (DMF), and 2.00 g of potassium carbonate were added into a 100 mL single neck flask, under stirring at room temperature, 1.20 g of 2-chloro-5-ethylaminomethylthiazole, prepared according to the example 1, in 5.0 mL DMF were added dropwise. After that, the reaction solution was heated to 40-80° C. and then reacted for 3-6 hr. After cooling down, the resulting mixture was added to water (50 mL), then treated by the method according to the example 1 to obtain 1.27 g of 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, as a golden yellow solid, having the content of 98.6%, a yield of 58.3%, and the structure was confirmed by GC-Mass and 1H NMR.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:12]1[O:22][C:16]2([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:15][CH:13]1[CH3:14]>>[CH2:12]1[O:22][C:16]2([CH2:21][CH2:20][N:19]([C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17]2)[O:15][CH:13]1[CH3:14]
Reactant: COC(=O)c1ccccc1F
Reactant: CC1COC2(CCNCC2)O1
Product: COC(=O)c1ccccc1N1CCC2(CC1)OCC(C)O2
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A mixture of methyl 2-fluorobenzoate (16.0 g, 103.8 mmol) and 4-piperidone propylene ketal (9.8 g, 62.3 mmol) was stirred at room temperature (8 d). Flash chromatography on silica gel (10% MeOH-90% CHCl3) afforded the title compound (44).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:3].C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:9][N:10]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CN(C)Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc(Oc2ccncc2[N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 6-((dimethylamino)methyl)pyridin-3-ol in DMF (5 mL) was added, K2CO3 (834.8 mg, 6.040 mmol) and the mixture was stirred at RT for 10 min before 4-chloro-3-nitro-pyridine (191.5 mg, 1.208 mmol) was added. The mixture was stirred at RT for 60 h. The reaction mixture was partitioned between EtOAc and NH4Cl aq satd. Combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo yielding an oil that purified by SCX column, yielding N,N-dimethyl-1-(5-((3-nitropyridin-4-yl)oxy)pyridin-2-yl)methanamine as a colourless oil. MS (ES+) 275.1.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[OH:13])=[CH:4][CH:3]=1.[CH3:16][O:17][C@@:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:22]([F:25])([F:24])[F:23])[C:19](Cl)=[O:20]>>[CH2:1]([N:10]1[CH2:11][CH2:12][C@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=2)[C@H:8]([O:13][C:19](=[O:20])[C@:18]([O:17][CH3:16])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([F:25])([F:24])[F:23])[CH2:9]1)[C:2]1[CH:15]=[CH:14][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC2CCNCC2O)cc1
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Product: CO[C@@](C(=O)O[C@@H]1CN(Cc2ccccc2)CC[C@@H]1Cc1ccc(C)cc1)(c1ccccc1)C(F)(F)F
Yield: 36 %

Procedure:
The title compound was prepared from (3SR,4SR)-4-(4-methyl-benzyl)-piperidine-3-ol and (S)-(+)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride in 36% yield as a yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:15])[CH2:13]I)[CH2:3]1.[N:26]1([C:31]2[N:36]=[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[CH:34]=[C:33]([N:43]3[CH2:47][CH2:46][CH2:45][CH2:44]3)[N:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[OH:1][C@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][C@@H:10]([CH3:25])[C@@H:11]2[C:12](=[O:15])[CH2:13][N:40]2[CH2:41][CH2:42][N:37]([C:35]3[CH:34]=[C:33]([N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[N:32]=[C:31]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:36]=3)[CH2:38][CH2:39]2)[CH2:3]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CI
Reactant: c1c(N2CCCC2)nc(N2CCCC2)nc1N1CCNCC1
Solvent: CN(C)C=O
Product: C[C@@H]1C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1

Procedure:
3β-Hydroxy-21-iodo-16α-methylpregn-5-en-20-one (10 g) is added all at once to 4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]piperazine (16 g) in DMF (400 ml) at 65° and then concentrated to 50 ml under reduced pressure. The concentrate is added to sodium dihydrogen phosphate (0.3M, 400 ml) and ethyl acetate (500 ml). The pH is adjusted to 4.5 with 0.3M phosphoric acid. The ethyl acetate layer is separated and extracted with sodium dihydrogen phosphate (0.3M, 2×200 ml). The ethyl acetate extract is then washed with phosphoric acid (0.3M, 400 ml). The acid extract is stirred and the ph is adjusted to 3.5 with sodium hydroxide (10%). The resulting precipitate is filtered, washed with water (200 ml) and dried to give the title compound.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:9]([OH:10])[C:8]=1O>>[CH3:6][C:7]1[CH:8]=[C:9]([OH:10])[CH:11]=[C:12]([CH3:14])[C:13]=1[OH:2]
Reactant: Cc1cc(C)c(O)c(O)c1
Reactant: O=S(=O)(O)O
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 1.10 g. of strong acidic sulfonic type ion exchange resin Amberlist 15 (manufactured by Rohm & Haas Co.) was used instead of sulfuric acid, 2.88 g. (20.9 m. moles) of 3,5-dimethylcatechol and 1.74 g. (12.6 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenols was 65.9 percent.
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:29](=[O:33])([O:31][CH3:32])[NH2:30]>C1(C)C=CC=CC=1>[CH3:32][O:31][C:29]([NH:30][C:2]1[C:3](=[O:5])[O:4][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH:6]=1)=[O:33]
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Reactant: COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Temperature: 105 °C
Yield: 94 %

Procedure:
300 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid, 2680 ml of toluene, 13.4 g of p-toluenesulfonic acid and 133.8 g of methyl carbamate are placed into a 6 l 4-necked round-bottomed flask in an oil-bath, the mixture is heated to 105° C. for 4 hours with stirring, and the present water is removed azeotropically, the mixture is filtered and the solution is evaporated to dryness under vacuum, then the residue is triturated for about 2 hours with 1260 ml of Et2O, filtered washing with petroleum ether (40-70° C.) and dried under vacuum at 60° C. 313.00 g are obtained. (Yield 94%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CCN(C(C)C)C(C)C.[CH2:19]([O:21][C:22](=[O:44])[C@@H:23]([CH3:43])[CH2:24][CH:25]([N:40]=[C:41]=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[CH:29][CH:28]=1)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:44])[C@@H:23]([CH3:43])[CH2:24][CH:25]([NH:40][C:41]([NH:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:42])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)=[CH:29][CH:28]=1)[CH3:20]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)N=C=O
Reactant: CC(C)(C)OC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Next, to a solution of tert-butyl 2-aminoacetate (140 mg, 1.065 mmol) in DMF (5 mL) is added DIEA (344 mg, 2.66 mmol). The solution is stirred at room temperature for 5 minutes then (S)-5-(3′-chloro-biphenyl-4-yl)-4-isocyanato-2-methyl-pentanoic acid ethyl ester (330 mg, 0.887 mmol) is added. The mixture is stirred at room temperature for 2 hours then the solvent is removed under reduced pressure to give (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester which is used directly in the following reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[C:16](=[O:21])[CH2:15]2)[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:3]([CH3:22])[C:4]([N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[C:16](=[O:21])[CH2:15]1)=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(N2CCN(C)C(=O)C2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(C)C(=O)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-1-methylpiperazin-2-one (31.0 mg, 0.095 mmol) and 5-morpholinopyridin-3-amine in toluene to give 4-(5,7-difluoro-3-methyl-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-1-methyl-2-piperazinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.95 (1H, br. s.), 7.71 (1H, br. s.), 7.31 (1H, ddd, J=9.8, 2.6, 1.3 Hz), 6.94 (1H, d, J=13.1 Hz), 6.83 (1H, ddd, J=13.9, 8.6, 2.5 Hz), 6.60 (1H, s), 4.07 (2H, s), 3.84-3.91 (4H, m), 3.67 (2H, t, J=5.4 Hz), 3.53 (2H, t, J=5.4 Hz), 3.13-3.21 (4H, m), 3.03 (3H, s), 2.08 (3H, s). Mass Spectrum (ESI) m/e=469.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][Si](C)(C)C>>[CH3:12][Si:13]([CH3:20])([CH3:19])[NH:14][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: C[Si](C)(C)NS(=O)(=O)c1ccc(F)cc1
Temperature: 115 °C

Procedure:
A glass reactor equipped with a stirrer, reflux condenser and gas inlet was charged with solid 4-fluorobenzenesulfonyl chloride 0.250 mol, 49.65 g). Hexamethyldisilazane (0.263 mol, 56.6 ml) was added to the reactor and the mixture was gradually heated with stirring to a temperature of 115° C., at which time it became clear. The mixture was then heated at the boiling point for 21 hours. Analysis of the mixture by 1H NMR indicated that the reaction was about 50% complete. Volatile materials were then removed by heating at a temperature of 65° C. under reduced pressure to yield a brown liquid which was distilled to remove unreacted sulfonyl chloride. The residue was redistilled under a pressure of 0.03 mm. Hg. The fraction collected from 40° to 97° C. was analyzed by 1H NMR and was found to contain the N-mono- and N,N-bis(trimethylsilyl)sulfonamides in a 1:1 molar ratio. Using the same analytical technique a second fraction collected within the range from 97° and 122° C. was found to contain the N-mono- and N,N-bis(trimethylsilyl)sulfonamides in a 8.5:1 molar ratio. The second fraction was used as the starting material (3c) for the subsequent reaction.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].C1COCC1.P(OCC)(OCC)([S-])=[S:25]>O>[C:1]([C:3]1[C:4]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:25])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(CC2CCC2)cc1C
Reactant: CCOP(=S)([S-])OCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(CC2CCC2)cc1C
Temperature: 80 °C
Reaction time: 48 h
Yield: 21 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-4-(cyclobutylmethyl)-2-methylbenzoate (compound 189.3, 5.00 g, 20.6 mmol, 1.00 equiv) in a solvent mixture of THF and H2O (50 mL/25 mL). O,O′-diethyl dithiophosphate (15.0 g, 80.5 mmol, 4.00 equiv) was added to the reaction flask. The resulting solution was stirred at 80° C. for 48 h (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the reaction was carefully quenched with 50 mL of brine. The mixture was extracted with 3×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:4) as eluent to furnish 1.20 g (21%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]C(=O)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
2.15 g 4-Acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (272) were dissolved in 84 ml MeOH and treated with 2.1 g (55.5 mmol) sodium borohydride at 0° C. after stirring for 2 h at RT all volatiles were removed in vacuo and to the residue was added slowly water and 2.3 g (11 mmol) citric acid monohydrate. Extraction with dichloromethane, drying with Sodium sulfate and evaporation gave 1.78 g of crude 4-Mercapto-piperidine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:14]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[NH2:14]
Reactant: COCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COCc1ccc(C(F)(F)F)cc1N
Yield: 91.7 %

Procedure:
0.15 g (0.638 mmol) of 1-methoxymethyl-2-nitro-4-trifluoromethylbenzene is added, at a temperature in the region of 25° C., to a suspension of 0.02 g (0.188 mmol) of 10% palladium-on-charcoal in 20 cm3 of methanol. After hydrogenation for 3 hours in an autoclave under 1 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with 3 times 5 cm3 of methanol, and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa), to give 0.12 g of 2-methoxymethyl-5-trifluoromethylphenylamine in the form of a yellow oil;
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH2:7][C@@H:8]([N:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11][C:12]([O:14]CC)=O)C)C.[CH2:25](O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:17]([N:10]1[CH2:8][C@@H:7]([CH3:6])[CH2:25][C:12](=[O:14])[CH2:11]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Reactant: CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 6.4 g, 14 mmol) in toluene (90 ml) was added (S)-3-(benzyl-ethoxycarbonylmethyl-amino)-butyric acid ethyl ester (20.3 g, 0.06 mol) in toluene (10 ml), followed by ethanol (1 ml). A vigorous reaction ensued, after 15 minutes the reaction was diluted with ethyl acetate, washed with 10% aq. citric acid solution, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (ethyl acetate/heptane 1:9) affording a complex mixture of diastereomers (7.2 g, 42%). A portion of this material (3.5 g, 13 mmol) was dissolved in 25% aq. hydrochloric acid solution (20 ml) and heated in a loosely closed tube at 120° C. for 36 h. The solvent was evaporated, the residue redissolved in dichloromethane, washed with sat. aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 1:4) afforded the titled product as a crystalline solid (1.1 g, 43%). MS (ISP)=204.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: O=C1CCC1
Reactant: Fc1cc(F)cc(Br)c1
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of 1-bromo-3,5-difluorobenzene (1.0 equiv.) in THF (0.26 M) under Ar was added Mg turnings (1.6 equiv.). A reflux condenser was attached and the solution was submerged in a 90° C. oil bath and refluxed for two hours. The cyclobutanone (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar for 5 hrs. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 1-(3,5-difluorophenyl)cyclobutanol in 54% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.69-1.83 (m, 1 H), 2.03-2.13 (m, 1 H), 2.31-2.43 (m, 2 H), 2.45-2.56 (m, 2 H), 6.71 (tt, J=8.80, 2.35 Hz, 1 H), 6.98-7.07 (m, 2 H).