Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Product: O=C(Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-benzyloxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.13 (bs, 1H), 9.00 (d, J=3.0, 1H), 8.83 (d, J=9.3, 1H), 8.23-8.20 (m, 1H), 7.85 (d, J=3.0, 1H), 7.53-7.46 (m, 1H), 7.44-7.37 (m, 6H), 5.15 (s, 2H).
Reaction SMILES: CN1CCNCC1.[Li]CCCC.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=[CH:14]1.CN(C)CCN(C)C.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>CCCCCC.C1COCC1>[CH2:41]([Sn:36]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:37][CH2:38][CH2:39][CH3:40])[C:14]1[O:13][C:17]2[CH:18]=[CH:19][C:20]([CH:22]=[O:23])=[CH:21][C:16]=2[CH:15]=1)[CH2:42][CH2:43][CH3:44]
Reactant: O=Cc1ccc2occc2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CN(C)CCN(C)C
Agent: CN1CCNCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 33.8 %

Procedure:
To a solution of N-methylpiperazine (0.75 g, 7.5 mmol) in hexane (15 mL) at 0° C. under nitrogen was added dropwise a solution of n-BuLi (3 mL, 7.43 mmol, 2.5M/hexanes), and the reaction mixture was stirred at 0° C. for 40 min. 1-Benzofuran-5-carbaldehyde (1.0 g, 6.8 mmol) was added dropwise to the reaction mixture at 0° C. and the resulting mixture was stirred at 0° C. for 15 min. After addition of tetramethylethylenediamine (TMEDA) (1.7 g, 14.96 mmol), a solution of n-BuLi (6.0 mL, 14.86 mmol, 2.5M/hexanes) was added dropwise to the reaction mixture at 0° C. and the reaction mixture was allowed to warm up to room temperature and stirred for a total of 18 h. After the reaction mixture was cooled to 0° C. and THF (30 mL) was added, the reaction mixture was cooled to −50° C., tributyltin chloride (4.87 g, 14.96 mmol) was added dropwise, and the reaction mixture was stirred at −50° C. for 15 min. and at room temperature for 5-6 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted into diethyl ether. The organic layer was dried over sodium sulfate and concentrated and the crude product was purified by column chromatography (ethyl acetate/hexane, 2%) to give 1.0 g (34%) of 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:39])=[O:2])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH:30][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:32])=[CH:28][CH:29]=1)=[O:22])[CH:19]([CH3:21])[CH3:20])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2ccccc2)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(NC(=O)c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-valyl-4-(phenylcarbonylamino)-L-phenylalanine methyl ester (0.500 g, 0.94 mmol) in dioxane (30 ml) is added lithium hydroxide monohydrate (0.084 g, 2 mmol) in water (10 ml). The reaction is stirred at room temperature overnight. The mixture is taken off in water (20 ml) and washed twice with ethyl acetate (2×20 ml). The aqueous phase is acidified until pH ~2 with 1N hydrochloric acid and extracted three times with ethyl acetate (3×20 ml). The organic layer is dried over anhydrous magnesium sulphate. After filtration and remtial of the solvent invacuo the title compound is obtained as a white solid (0.400 g, 82% yield). MS: [MH]+ =518 [MNH4 ]+ =535.
Reaction SMILES: [NH2:1][C@:2]([CH3:13])([CH2:5][CH2:6][C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:15].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cn1cccc1CC[C@@](C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cccc1CC[C@]1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
The obtained (2R)-2-amino-2-methyl-4-(1-methylpyrrol-2-yl)butan-1-ol 1/2 D-(−)-tartrate (41.4 mg, 0.16 mmol) was suspended in methylene chloride (1.6 mL) and di-t-butyl dicarbonate (0.176 g, 0.810 mmol), triethylamine (0.225 mL, 1.62 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) were added thereto, followed by stirring of the mixture at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate 3:2-2:1) to obtain (4R)-4-methyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (17.7 mg, yield: 53%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([NH:38][C:21]([C:20]2[N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:12](=[O:31])[C:13]3[C:18]([C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=3)=[O:22])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: O=C(NC1CCCCC1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and cyclohexylamine. Colorless crystals (130 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[S:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[CH2:23][C:22](=[O:33])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccc(C#N)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)s1

Procedure:
Prepared from {3-[3-(5-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K69) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (263 mg).
Reaction SMILES: [F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8]OC)[C:4]#[N:5].C[Si]([I:26])(C)C>C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([CH2:6][CH2:7][CH2:8][I:26])[C:4]#[N:5]
Reactant: COCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O

Procedure:
2-Fluoromethyl-2-phthalimido-5-methoxy-valeronitrile (1.20 g, 4.14 mmol), trimethylsilyl iodide (3.2 g, 16 mmol) and chloroform (15 ml) are heated to 60° C. under nitrogen for 48 hours. After removal of the solvent, the residue is dissolved in chloroform, washed with water, sodium thiosulfate solution and water again, dried and evaporated to give the crude product as an oil (1.2 g). This is purified by chromatography on silica (ethyl acetate/petroleum ether 1:3) to give pure 2-fluoromethyl-2-phthalimido-5-iodo-valeronitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:59])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:56][CH2:57][CH3:58])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[C:37]([O:39]CC4C=CC=CC=4)[C:36]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[CH:35][C:34]=3[CH2:54][CH3:55])=[CH:23][CH:24]=2)[O:19]1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12](=[O:59])[CH2:13][CH2:14][NH:15][C:16]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[C:21]([CH2:56][CH2:57][CH3:58])[C:22]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]3[C:34]([CH2:54][CH3:55])=[CH:35][C:36]([C:47]4[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=4)=[C:37]([OH:39])[CH:38]=3)=[CH:23][CH:24]=2)[O:19]1)=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCC(=O)OCCNC(=O)OC(C)(C)C)CC2
Yield: 81.8 %

Procedure:
2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(2-ethyl-4-(4-fluorophenyl)-5-(phenylmethoxy)phenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate (110 mg) was dissolved in methanol/chloroform (2:1, 5 mL) with 10% Pd/C (24 mg) and hydrogen gas bubbled in for 2 hours. The mixture was filtered through Celite®, rinsed with methanol, and concentrated under vacuum to afford 80 mg of 2-((tert-butoxy)carbonylamino)ethyl-3-((7-(3-(6-ethyl-4-(4-fluorophenyl)-3-hydroxyphenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propanoate. Mass Spec (EI): 723.5 (M+H).
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:22][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCCCCCO
Agent: [Na]
Product: CCCCCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of sodium (350 mg, 15 mmol) in 1-octanol (10 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol). The mixture was stirred at 50° C. for 1 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[C:26](=[O:31])[CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: CN1CCNCC1=O
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: Cl
Product: CN1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)CC1=O

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Intermediate J, 50 mg, 0.160 mmol) and 1-methylpiperazin-2-one hydrochloride (36.5 mg, 0.320 mmol) (tR 3.11 min (conditions 5), MH+=391, 1H-NMR in DMSO-d6: 8.84 (d, 1H); 8.33 (d, 1H); 7.95 (s, 1H); 7.85 (d, 1H); 7.71 (d, 1H); 7.48 (m, 1H); 7.46 (s, 1H); 7.15 (d, 1H); 4.42 (s, 2H); 4.06 (s, 2H); 3.75 (m, 2H); 3.49 (m, 2H); 2.83 (m, 3H)).
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[N:5][N:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.C(N(C(C)C)CC)(C)C.[C:21]1([C:27]2[N:28]=[C:29]3[N:34]=[C:33]([NH2:35])[CH:32]=[CH:31][N:30]3[CH:36]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[C:21]1([C:27]2[N:28]=[C:29]3[N:34]=[C:33]([NH:35][C:9]([C:3]4[N:4]([CH3:8])[N:5]=[C:6]([CH3:7])[C:2]=4[Cl:1])=[O:11])[CH:32]=[CH:31][N:30]3[CH:36]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: Cc1nn(C)c(C(=O)O)c1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
4-Chloro-2,5-dimethyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.57 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) were added to a solution of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 100 mg, 0.48 mmol) in ethyl acetate (3 ml). At 0° C., propylphosphonic acid anhydride (1-propanephosphonic acid cyclic anhydride, 50% in ethyl acetate, 0.7 ml, 2.5 eq.) was added dropwise to the mixture. After stirring for 30 min at 0° C., the mixture was stirred overnight at RT. The mixture was taken up in ethyl acetate, washed (water), dried (Na2SO4), and concentrated under reduced pressure. The title compound (16 mg, 9%) was obtained from the residue by preparative HPLC (254 nm, Agilent Zorbax XdB-C18, Run: 7 min, Flow: 30 ml/min, Gradient: 0.0 min: 95/5 H2O/CH3CN; 0.5 min: 95/5 H2O/CH3CN 4.5 min: 5/95 H2O/CH3CN; 6.9 min 5/95 H2O/CH3CN; 7 min 95/5 H2O/CH3CN).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][N:12]2[C:18](=[O:19])[C@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][S:15](=[O:29])(=[O:28])[C@@H:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:13]2)[CH2:10][CH2:9]1>ClCCl>[NH2:20][C@@H:17]1[CH2:16][S:15](=[O:29])(=[O:28])[C@@H:14]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13][N:12]([CH2:11][CH:8]2[CH2:10][CH2:9]2)[C:18]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CS(=O)(=O)[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CS(=O)(=O)[C@@H](c2ccccc2)CN(CC2CC2)C1=O
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to a solution of tert-butyl (2S,6S)-4-(cyclopropylmethyl)-1,1-dioxido-5-oxo-2-phenyl-1,4-thiazepan-6-ylcarbamate (63 mg, 0.167 mmol) in dichloromethane (5 mL). After 1 h, the mixture was concentrated and aqueous saturated sodium bicarbonate was added. The mixture was extracted with dichloromethane (2×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the crude product (50 mg).
Reaction SMILES: [NH2:1][CH:2]([P:6](=[O:11])([O:9][CH3:10])[O:7][CH3:8])[CH:3]([CH3:5])[CH3:4].C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[C:30]([CH2:34][CH2:35][C:36](Cl)=[O:37])([O:32][CH3:33])=[O:31]>N1C=CC=CC=1>[C:30]([CH2:34][CH2:35][C:36]([NH:1][CH:2]([P:6](=[O:11])([O:7][CH3:8])[O:9][CH3:10])[CH:3]([CH3:5])[CH3:4])=[O:37])([O:32][CH3:33])=[O:31]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COP(=O)(OC)C(N)C(C)C
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)NC(C(C)C)P(=O)(OC)OC
Temperature: 0 °C

Procedure:
To a solution of a compound of formula 3, preferably dimethyl (1-amino-2-methylpropyl)phosphonate, in an anhydrous polar aprotic solvent, preferably pyridine, is added a tertiary amine, preferably a mixture of tertiary amines, and most preferably, a mixture of diisopropylethylamine and dimethylaminopyridine. The mixture is cooled, preferably to 0° C, and a carboalkoxyalkyl halide, preferably carbomethoxypropionyl chloride is added. The reaction is allowed to stir until the reaction is complete. The product, a compound of Formula 4, preferably dimethyl [1-[N-(3-carbomethoxypropionyl)amino]-2-methylpropyl]phosphonate, may be isolated and purified by conventional means.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=Cc1cc2cccc(Cl)c2nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F

Procedure:
Prepared according to Procedure A using 2,8-dichloroquinoline 3-carbaldehyde (1.0 g, 4.42 mmol), 2-trifluoromethylphenyl boronic acid (0.924 g, 4.87 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (0.256 g, 0.221 mmol, 0.05 eq), and sodium carbonate (2.34 g, 22.1 mmol, 5 eq) in acetonitrile (30 mL) and water (10 mL). After purification, 2-(2-trifluoromethylphenyl)-8-chloroquinoline-3-carbaldehyde was obtained as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.95 (1 H, s), 9.19 (1 H, s), 8.33 (1 H, dd, J=8.5, 1.2 Hz), 8.20 (1 H, dd, J=7.3, 1.2 Hz), 7.95 (1 H, d, J=7.3 Hz), 7.74-7.87 (2 H, m), 7.63 (1 H, d, J=7.3 Hz) Mass Spectrum (ESI) m/e=336.1 and 338.0 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[S:4][N:3]=1.[Br:25]Br>C(Cl)Cl.CC(O)=O>[Br:25][C:6]1[C:2]([CH3:1])=[N:3][S:4][C:5]=1[N:7]([C:17]([O:19][CH2:20][C:21]([Cl:23])([Cl:24])[Cl:22])=[O:18])[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1cc(C)ns1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1snc(C)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate (28.5 g, 68 mmol) in CH2Cl2 (250 mL) and AcOH (125 mL) was added bromine (8.5 mL, 165 mmol). The resulting red solution was stirred at room temperature for 4 h. A further aliquot of bromine (8.5 mL, 165 mmol) was added and the resulting solution was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc and water+aqueous NaHSO3 until the decolorization was complete. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc in hexane to afford methyl N-(4-bromo-3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate as a yellow syrup.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([Cl:21])=[CH:11][C:12]([O:18][CH2:19][CH3:20])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:24])=[N-]>O1CCCC1>[CH3:24][O:15][C:14](=[O:16])[C:13]1[CH:17]=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([Cl:21])=[CH:11][C:12]=1[O:18][CH2:19][CH3:20]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C(=O)O
Solvent: C1CCOC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C(=O)OC
Reaction time: 0.5 h

Procedure:
5-tert-Butylsulfamoyl-4-chloro-2-ethoxybenzoic acid (0.8 g, 24 mmol) in 10 mL of tetrahydrofuran was treated with diazomethane (15 mL, ˜2-3 M in ether, prepared from N-methyl-N-nitroso-p-toluenesulfonamide, Aldrich) at room temperature and stirred for 0.5 h. The mixture was concentrated, and the residue was purified by flash chromatography (silica gel, eluting with 20% ethyl acetate in hexane) to give 0.45 g of 5-tert-butylsulfamoyl-4-chloro-2-ethoxybenzoic acid methyl ester as a solid.
Reaction SMILES: [C:1]1([C:7](=[O:14])[C:8](=[N:12]O)[C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16][O:17][C:18]([CH2:20][C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=O)=[O:19].C([O-])(=O)C.[Na+]>[Zn].O.C(O)(=O)C>[C:7]([C:8]1[NH:12][C:21]([CH2:20][C:18]([O:17][CH2:16][CH3:15])=[O:19])=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:9]=1[CH3:10])(=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=NO)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1[nH]c(C(=O)c2ccccc2)c(C)c1C(=O)OCC
Temperature: 100 °C

Procedure:
A solution of 71 g. (0.37 mole) of 1-phenyl-1,2,3-butanetrione-2-oxime in 350 ml. glacial acetic acid and 50 ml. of water is added to 75.5 g. diethyl acetonedicarboxylate in 350 ml. of glacial acetic acid at 70° C. Concurrently, a mixture of 73 g. (1.12 mole) of zinc dust and 91.5 g. (1.12 mole) of anhydrous sodium acetate is added in portions at such a rate that the temperature is maintained near 100° C. After the additions are complete (about 45 minutes), the mixture is refluxed for one hour and poured into iced water. The resulting crude semisolid is collected by filtration and recrystallized twice from methanol to give ethyl 5-benzoyl-3-ethoxycarbonyl-4-methylpyrrole-2-acetate, m.p. 152-154° C. Analysis: Calcd. for C19H21NO5 : C, 66.46; H, 6.16; N, 4.08%. Found: C, 66.50; H, 6.20; N, 4.17%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(N(CC)CC)C.[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>CO>[F:17][C:18]([F:25])([F:24])[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:20]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCCC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h
Yield: 84 %

Procedure:
6-Aminocaproic acid (1, 6.55 g, 50 mmol) was suspended in methanol (30 ml) and treated with triethylamine (6.9 ml, 100 mmol) followed by ethyl trifluoroacetate (7.2 ml, 60 mmol). The mixture was stirred at room temperature (r.t.) during 40 hours. The unreacted solid precipitate was filtered, the filtrate was evaporated in vacuo and crystallized from benzene-hexane mixture. Trifluoroacetyl derivative (2) had an 84% yield (9.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccc(F)cc1)N1CCOCC1
Product: O=C(NCC(c1ccc(F)cc1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]4[CH:17]=[C:18]5[C:24](=[CH:25][CH:26]=4)[C:21]4([CH2:23][CH2:22]4)[N:20](C(=O)C(F)(F)F)[CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([O:37]CC)=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCOCC1>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:33])=[C:11]([C:16]4[CH:17]=[C:18]5[C:24](=[CH:25][CH:26]=4)[C:21]4([CH2:22][CH2:23]4)[NH:20][CH2:19]5)[C:12]=3[O:14][CH3:15])[C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(-c3ccc4c(c3)CN(C(=O)C(F)(F)F)C43CC3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1c(-c2ccc3c(c2)CNC32CC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a suspension of 210 mg of ethyl 1-cyclopropyl-6-fluoro-8-methoxy-7-[2-trifluoroacetyl-spiro[isoindolin-1,1'-cyclopropan]-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate in 4.2 ml of ethanol were added 2.1 ml of 1N aqueous sodium hydroxide solution and 4.2 ml of dioxane, after which the resulting mixture was heated with stirring at 40° C. for three hours. The reaction mixture was cooled to room temperature, and thereafter, insolubles were removed by filtration, after which a carbon dioxide gas was blown in the filtrate obtained. The crystals precipitated were collected by filtration, to obtain 140 mg of pale yellow, crystalline 1-cyclopropyl-6-fluoro-8-methoxy-7-[spiro[isoindolin-1,1'-cyclopropan]-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.