Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[C:27]1([CH:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:9](=[O:11])[CH:8]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCNC(=O)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Product: O=C(C=Cc1cccnc1)NCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
Batch size: 2.0 g (13.4 mmol) 3-(3-pyridyl)-acrylic acid, 3.0 g (29.6 mmol) TEA, 2.4 g (15.6 mmol) 88% HOBT, 3.0 g (15.6 mmol) EDC and 4.0 g (13.4 mmol) 4-diphenylacetylamino-butylamine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>CC(C)=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)=[CH:3][C:2]=1[O:1][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(O)c2)n1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2ccc(OC)c(OCC=C(C)C)c2)n1
Yield: 42 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxy-4-methoxyphenylamino)thiazole-4-carboxylate (139 mg, 0.47 mmol) and K2CO3 (72 mg, 0.52 mmol) in acetone (4.7 mL) was treated with 4-bromo-2-methyl-2-butene (0.066 mL, 0.56 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 42% yield (71 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[CH2:26]([NH:29][CH2:30][CH:31]=[CH2:32])[CH:27]=[CH2:28]>>[CH2:26]([N:29]([CH2:30][CH:31]=[CH2:32])[C:19](=[O:21])[C:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:24])[C:9]([CH3:25])=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:22])[CH3:23])[CH:27]=[CH2:28]
Reactant: C=CCNCC=C
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Product: C=CCN(CC=C)C(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
The above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methyl-propanoic acid and diallylamine using a procedure analogous to that of Example 130.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:23][C:24]([O:26]CC)=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:37][NH2:38]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:23][C:24](=[O:26])[NH:38][N:37]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)CC(C(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C3=NNC(=O)CC3c3ccccn3)cc2)CC1
Yield: 54.8 %

Procedure:
A solution of the product from step 3 (4.0 g, 8.3 mmol) and hydrazine hydrate (0.83 g, 16 mmol) in 30 mL of EtOH was stirred at 90° C. overnight. The yellow suspension was reduced to ˜15 mL of EtOH. The solid was collected and washed with cold EtOH to give the product (2.05 g, 55%): Mp 213-214° C.; MS m/z 395 (M-tBu+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=2[CH3:9])=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Product: Cc1nc(NC(=O)C(C)(C)C)ccc1COCc1ccc(F)cc1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.6 g, product of example 112 step B]) and 4-fluorobenzyl bromide (0.56 g) as an orange solid (0.8 g). MS (ESI): 231.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=2)[N:13]([CH3:21])[N:12]=1.[S:22](=O)(=[O:25])([OH:24])[OH:23]>>[NH2:20][C:16]1[N:15]=[C:14]2[N:13]([CH3:21])[N:12]=[C:11]([C:4]3[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([S:22]([OH:25])(=[O:24])=[O:23])[CH:5]=3)[C:19]2=[CH:18][N:17]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)c(OC)c1
Product: COc1cc(OC)c(S(=O)(=O)O)cc1-c1nn(C)c2nc(N)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 89) (1 g, 3.50 mmol) is dissolved in concentrated sulfuric acid (25 ml) to give a blood red solution. The reaction mixture is stirred at room temperature overnight, poured onto ice-water (200 ml) and the resulting solid is collected by filtration, washed with water and dried under vacuum to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:26][CH:23]1[CH2:24][CH2:25][CH:20]([CH3:19])[CH2:21][CH2:22]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC1CCC(N)CC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 4-methyl-cyclohexylamine following general procedure B to afford 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (290 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (200 mg) following general procedure E. The above ethylamide (0.41 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (22 mg). LCMS: m/z 368 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[C:3]=1[Cl:11].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.C(Cl)(=O)C>C(OCC)C>[Cl:11][C:3]1[C:4]([O:9][CH3:10])=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: COc1c(Cl)ccc(Br)c1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: CCOCC
Product: COc1c(Cl)ccc(B(O)O)c1Cl
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 1-bromo-2,4-dichloro-3-methoxybenzene (5.12 g, 20 mmol) in diethyl ether cooled to −70° C. was added 2.5M n-butyl lithium (8.8 mL, 22 mmol) in portions keeping the temperature below −60° C. The resulting reaction mixture was then stirred for 10 minutes before triisopropylborate (6.9 mL, 30 mmol) was added in portions keeping the temperature below −60° C. The reaction mixture was then allowed to warm to room temperature and acetyl chloride (60 mmol) was added. The reaction mixture was stirred for an hour at room temperature and concentrated. The residue was partitioned between ethyl acetate and 1N NaOH (40 mL) and the organic phase was extracted with additional 1N NaOH (10 mL). The sodium hydroxide extracts were combined, ice was added, and the solution was acidified to pH 3-4 with concentrated HCl. The product was then extracted with ethyl acetate and the organic phase was dried and concentrated to yield 2,4-dichloro-3-methoxyphenylboronic acid (3.27 g, 14.8 mmol): 1H NMR (CDCl3): δ 8.44 (br s, 2H), 7.42 (d, 1H), 7.15 (d, 1H), 3.8 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([C:29]([OH:31])=O)=[C:27]([CH3:32])[S:26][C:25]=3[CH:33]=2)[CH:12]=1)=[O:10].[NH2:34][CH2:35][CH2:36][CH2:37][OH:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[OH:38][CH2:37][CH2:36][CH2:35][NH:34][C:29]([C:28]1[C:24]2[CH:23]=[CH:22][C:21]([O:20][C:17]3[CH:16]=[CH:15][N:14]=[C:13]4[CH:12]=[C:11]([C:9]([N:5]5[CH2:6][CH2:7][CH2:8][C@H:4]5[CH2:3][O:2][CH3:1])=[O:10])[S:19][C:18]=34)=[CH:33][C:25]=2[S:26][C:27]=1[CH3:32])=[O:31]
Reactant: NCCCO
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)O)c(C)sc4c3)c2s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NCCCO)c(C)sc4c3)c2s1
Yield: 87.7 %

Procedure:
This material was prepared by the reaction of 6-[(2-{[(2S)-2-(methoxymethyl)-pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylic acid 121b (45 mg, 0.093 mmole) with 3-amino-1-propanol (21 μL, 0.28 mmole), HBTU (53 mg, 0.14 mmole), and diisopropylethylamine (36 μL, 0.21 mmole) in a manner as previously described for example 117 to give a yellow solid (44 mg, 88%). 1NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.27 Hz), 8.36 (1H, t, J=5.46 Hz), 8.03 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.82 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=1.70, 8.67 Hz), 6.75 (1H, d, J=5.27 Hz), 4.51 (1H, t, J=5.18 Hz), 4.30 (1H, m), 3.85 (2H, m), 3.37 (2H, m), 3.27 (3H, s), 2.60 (3H, s), 2.09-1.83 (4H, m), 1.71 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-benzoic acid (72.0 g, 351 mmol) in MeOH (1000 mL) was added dropwise concentrated sulfuric acid (50 mL). The mixture was heated to reflux for 16 h under nitrogen, allowed to cool to r.t., and then concentrated in vacuo to ¼ of its volume. The mixture was taken up in EtOAc and washed with water, 10% aqueous solution of sodium carbonate, and brine. It was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by column chromatography (silica gel 60, hexanes/EtOAc 9:1) furnished 2-amino-4-trifluoromethyl-benzoic acid methyl ester (57.8 g, 264 mmol, 75%) as a white powder, m.p. 59° C., ESI-MS: m/z 218 [M−H]−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:40])[N:28]5[CH2:31][O:32][C:33]([CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[O:34])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:40])[N:28]5[CH2:31][O:32][C:33]([CH:35]5[CH2:36][CH2:37][CH2:38][CH2:39]5)=[O:34])=[CH:23][CH:22]=4)[CH2:14][CH2:15]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C(OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)C1CCCC1
Temperature: 25 °C
Yield: 15.1 %

Procedure:
To a solution (10 ml) of cyclopentanecarboxylic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester (252 mg) synthesized in the same manner as in Example 13 in THF was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (509 mg), and the mixture was stirred at room temperature stirred for 2 days. To the reaction mixture were added water and sodium carbonate, and the mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and further by NH silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) to give the title compound (yield 38 mg, 15%) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-])=O)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=[O:21])[CH3:20])[CH:3]=1.[H][H]>CO.[Pt]>[NH2:9][C:6]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:4]([C:19](=[O:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH3:8]
Reactant: [H][H]
Reactant: CC(=O)c1cc(Cl)c(C)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: [Pt]
Solvent: CO
Product: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Yield: 102.9 %

Procedure:
A mixture of 1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (4.4 g, 14 mmol) in methanol (80 mL) was hydrogenated in the presence of 5% Pt/C (443 mg) under balloon pressure of hydrogen overnight. The catalyst was filtered and the filtrate was concentrated under reduced pressure to give the desired product (4.0 g, 100%). LCMS calculated for C15H14ClFNO (M+H)+: m/z=278.1. found: 278.1.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[N:3]1[C:12]2[C:7](=[CH:8][C:9](I)=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([O:17]CCCC)=O)=[CH:4]1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:15]([C:5]2[C:6](=[O:14])[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:4]#[C:5][CH2:6][OH:14])[CH:8]=3)[N:3]([N:2]([CH3:1])[CH3:22])[CH:4]=2)=[O:17])=[CH:26][CH:25]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCCCOC(=O)c1cn(N(C)C)c2ccc(I)cc2c1=O
Product: CN(C)n1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Butyl 1-(dimethylamino)-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate (0.50 g) from Preparation No. 58 and 4-chlorobenzylamine (0.29 mL) are heated to 170° C. for 7 hours. The reaction is cooled to rt, and the crude solid is recrystallized in acetic acid yielding 0.54 g of the amide. The resulting amide (0.25 g), copper (I) iodide (30 mg), and bis(triphenylphosphine)palladium (II) chloride (18 mg) are suspended in diethylamine (8 mL). Propargyl alcohol (36 μL) is added and the mixture is allowed to stir at room temperature for 16 h. The mixture is diluted with ethanol and then concentrated in vacuo. The crude solid is triturated with dichloromethane and purified by column chromatography (2% MeOH/CH2Cl2), affording 9 mg of the title compound as a beige solid.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5]([OH:7])=[O:6].[C:11](OC(C)C)(=O)C>CO>[ClH:1].[CH3:11][CH:4]([C:5]([OH:7])=[O:6])[C@@H:3]([C:8]([OH:10])=[O:9])[NH2:2]
Reactant: CC(=O)OC(C)C
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: Cl
Solvent: CO
Product: CC(C(=O)O)[C@H](N)C(=O)O
Reaction time: 6.5 h

Procedure:
To methanol (500 ml) at 25°, gaseous HCl (0.89 mole) was bubbled into the solution over about 0.5 hr. L-Aspartic acid (0.77 mole) was added rapidly, then the resulting solution was held at 25° C. for 6.5 hrs. The methanol was stripped with an aspirator maintaining the pot temperature below 35° C. The batch became fairly thick when 145 ml (115 g) of methanol remained. Isopropyl acetate (435 ml) was added in about 0.5 hr, then the slurry was cooled to 0°-5° C. and held for 0.5 hr. Solid β-methyl-L-aspartate hydrochloride was collected and washed with 100 ml of isopropyl acetate. Dry wt.=100.2 g (70.6%) m.p. 192°-4°.
Reaction SMILES: [Na].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+].[F:14][C:15]([F:47])([F:46])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](O)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1>C(OCC)(=O)C>[F:14][C:15]([F:46])([F:47])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=1
Reactant: CCOC(=O)CC(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
The [4-(polyfluoroalkylamino)phenyl]alkenoic acids may be prepared by condensation of the appropriate aldehydes or by dehydration of the corresponding substituted-phenyl-hydroxyalkanoic acids. For example, ethyl 5-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-2,4-pentadienoate is obtained by the Wittig reaction of 4-[15-(trifluoromethyl)pentadecylamino]benzaldehyde with the Wittig reagent, triethyl 4-phosphonocrotonate. Alternatively, these alkenoic acids are obtained by heating 4-[N-polyfluoroalkyl-N-(methyl or acetyl)amino]benzaldehydes with the sodium salt of the carbanion of ethyl acetate or with a mixture of ethyl acetate, acetic anhydride and potassium acetate. The second method is illustrated by dehydration of ethyl 3-{4-[15-(trifluoromethyl)pentadecylamino]phenyl}-3-hydroxypropionate to yield ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CC#N>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 140 °C
Yield: 94.8 %

Procedure:
5-Nitro-2-chloropyridine (21) (350 mg, 2.21 mmol) and 1-Boc-piperazine (430 mg, 2.31 mmol) were dissolved in MeCN (3.6 mL). TEA (400 μL, 2.87 mmol) was added and the mixture heated at 140° C. in the microwave (250 W, stirring) for 30 minutes. The solvent was evaporated in vacuo and the residue dissolved in DCM (75 mL). The solution was washed with 0.5N HCl (2×20 mL) and the organic phase washed with saturated brine solution (40 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo to afford the title compound as a yellow solid (646 mg, 95%); LCMS, Rt=2.97 min (MeOH-FA method), m/z 309 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1.[C:24]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(=[O:26])[CH3:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:30]3[CH2:31][CH2:32][CH:28]([NH:27][C:24](=[O:26])[CH3:25])[CH2:29]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1
Reactant: O=C(O)c1cn(-c2ccncc2F)c2cc(F)c(F)cc2c1=O
Reactant: CC(=O)NC1CCNC1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccncc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.22 g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid and 0.11 g of 3-acetamidopyrrolidine are added to 12 ml of pyridine, and added with 0.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 24 hours, and then concentrated under a reduced pressure to remove the solvent completely. The residue is added with 20 ml of acetone and stirred at room temperature for 1 hour to obtain a product, which is then filtered and dried and used in the next reaction. (next reaction: Example 5)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[Cl:21][C:22]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:23]=1[NH2:24]>>[NH2:24][C:23]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:28][C:22]=1[Cl:21]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)c(Cl)c3)ccn2c1=O
Yield: 63.3 %

Procedure:
Methyl 8-(4-amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (76 mg, 0.26 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (78 mg, 0.31 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (63 mg, 62%). ESI-MS m/z: 387 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]=[C:8]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[NH:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.Cl[CH2:23][CH:24]=O.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:16]([CH:17]([CH3:19])[CH3:18])[CH:23]=[CH:24][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: O=CCCl
Reactant: CC(C)NC(=N)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 80 °C
Yield: 96.1 %

Procedure:
To a solution of 8-bromo-N-isopropyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxamidine (878 mg, 2.4 mmol) in THF (15 mL) was added chloroacetaldehyde solution (˜50 wt. % in H2O, 7.53 mL, 47.9 mmol) and aqueous saturated sodium bicarbonate solution (6 mL) at RT. The mixture was heated to 80° C. with rapid stirring. After heating for 20 hours the mixture was allowed to cool to RT and was extracted with DCM (150 mL). The organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (900 mg, 96%). LCMS RT=4.90 min, [M+H]+=390/392
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:22]([NH2:24])=O>>[O:8]=[C:7]1[NH:24][CH:22]=[N:1][C:2]2[S:3][C:4]3[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][C:5]=3[C:6]1=2
Reactant: NC=O
Reactant: CCOC(=O)CC1CCc2c(sc(N)c2C(=O)OCC)C1
Product: CCOC(=O)CC1CCc2c(sc3nc[nH]c(=O)c23)C1
Temperature: 180 °C
Yield: 68.4 %

Procedure:
Formamide (310 mL) was added to ethyl 2-amino-6-(2-ethoxy-2-oxoethyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (61.2 g, 197 mmol) and the biphasic mixture was heated at 180° C. in an oil bath overnight. The heat was turned off and the reaction solution was allowed to cool. At 60° C., the reaction mixture was seeded and lots of solid quickly precipitated. Upon reaching room temperature the reaction mixture was filtered (very slowly), and rinsed with water (2×150 mL). The damp solid was placed in a vacuum oven and dried at 50° C. overnight to yield a light tan solid (39.3 g, 68.4%). 1H NMR (DMSO-d6) δ 12.31 (s, 1H), 7.99 (s, 1H), 4.09 (q, 2H), 3.06 (m, 1H), 2.87 (m, 1H), 2.75 (m, 1H), 2.40 (m, 3H), 2.19 (m, 1H), 1.89 (m, 1H), 1.47 (m, 1H), 1.19 (t, 3H); LCMS RT=2.40 min, [M+H]+=293.1.