Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>O1CCOCC1>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][C:18]=3[C:4]=2[CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(I)cc3c2C1
Temperature: 70 °C

Procedure:
To a solution of compound 4-iodophenylhydrazine (1 equiv.) in 1,4-dioxane (50 mL) is added conc. sulfuric acid, followed by dropwise addition of 1-methyl-4-piperidone (1 equiv.) at RT. The reaction mixture is heated at 70° C. for 90 min., evaporated, diluted with water and the pH is adjusted to 12 with 40 mL of 15% aq. KOH solution. The reaction mixture is extracted with EtOAc, followed by brine wash, dried over sodium sulfate and evaporated under vacuum. The crude product is column purified over 230-400 silica gel using a gradient of 0-5% of MeOH in EtOAc. Note 1: The reaction temperature should be 70° C. Higher temperature results in the de-iodo carboline.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:13])[N:5]2[N:4]=1.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:31])C=1>>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:13])[N:5]2[N:4]=1)=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(C(O)c3ccccc3)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(C(O)c3ccccc3)n2n1
Yield: 48.2 %

Procedure:
(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol (0.340 g, 1.25 mmol) was dissolved in Methylene chloride (6 mL, 90 mmol) and the solution was treated with m-Chloroperbenzoic acid (0.379 g, 1.69 mmol) at room temperature. The reaction was allowed to stir until HPLC showed consumption of starting materials. The mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 173 mg of (2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.48 (m, 2H), 7.33 (m, 3H), 6.92 (m, 1H), 6.84 (m, 1H), 6.50 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH2:29])=[O:28])=[CH:25][CH:24]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:29][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=3)=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(c2ccc(I)cc2)COC1(C)C
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C(c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)COC1(C)C
Temperature: 110 °C
Yield: 69.5 %

Procedure:
A stirred suspension of (RS)-4-(4-iodo-phenyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (400 mg, Example 1e), 4-chlorobenzamide (185 mg), copper(I) iodide (20 mg), N,N′-dimethylglycine (20 mg) and potassium phosphate (1.05 g) in DMSO (2 ml) in a sealed tube was heated at 110° C. overnight. The mixture was then cooled to room temperature and was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (RS)-4-[4-(4-chloro-benzoylamino)-phenyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (297 mg, 69%) as a white solid. MS (ISP): 450.2 ([{37Cl}M+NH4]+), 448.2 ([{35Cl}M+NH4]+), 433.2 ([{37Cl}M+H]+), 431.2 ([{35Cl}M+H]+), 377.2 ([{37Cl}M+H—C4H8]+), 375.2 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [NH2:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>C(O)C>[CH2:24]([O:23][C:19]([CH2:20][CH2:21][NH:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:22])[CH3:25]
Reactant: CCOC(=O)C(C)C(N)Cc1ccccc1OC
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCNC(Cc1ccccc1OC)C(C)C(=O)OCC
Yield: 99.6 %

Procedure:
148 g (0.6 mol) of ethyl 3-amino-4-(2-methoxyphenyl)-2-methylbutanoate 13 and 119 g (1.2 mol) of ethyl acrylate are dissolved in 250 mL of abs. ethanol and refluxed for 6 h. Then the mixture is concentrated by evaporation in vacuo. The residue is again taken up in 300 mL of toluene and once more concentrated by evaporation in vacuo. 210 g (100%) of the desired product are isolated as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([Sn](C)(C)C)[CH:19]=2)=[CH:2]1.Br[C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42](=[O:43])[NH:41][C:39](=[O:40])[C:38]=12.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:40]=[C:39]1[C:38]2[C:37](=[CH:36][C:35]([C:18]3[CH:19]=[C:14]([O:13][CH2:12][C@@H:11]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH:15]=[N:16][CH:17]=3)=[CH:34][CH:33]=2)[C:42](=[O:43])[NH:41]1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc([Sn](C)(C)C)c1)Cc1c[nH]c2ccccc12
Reactant: O=C1NC(=O)c2c(Br)cccc21
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3c(c2)C(=O)NC3=O)c1)Cc1c[nH]c2ccccc12
Temperature: 75 °C
Yield: 73 %

Procedure:
A solution of Example 32A (0.2 g, 0.31 mmol) and 6-bromophthalimide (0.084 g, 0.4 mmol) in DMF (2 mL) was treated with Pd2dba3 (0.04 g, 0.02 mmol), tri-o-tolylphosphine (0.02 g, 0.01 mmol), and triethylamine (0.06 mL, 0.4 mmol). The reaction was heated to 75° C. for 6 hours in a sealed tube and concentrated. The residue was purified by flash column chromatography on silica gel with 1:1 hexanes/ethyl acetate to provide the desired product (0.116 g, 55%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=O.Cl.CO.P(Br)(Br)[Br:16]>ClCCl>[Br:16][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: CSc1cccc(C(=O)O)c1
Reactant: BrP(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CSc1cccc(CBr)c1
Reaction time: 8 h

Procedure:
A solution of 1.50 g (8.92 mmol) 3-(methylthio)benzoic acid (Aldrich) in 20 mL of dry dichloromethane is cooled to 0° C. and 1.86 mL (19.6 mmol) borane-methylsulfide complex (Aldrich) is added. The solution is allowed to reach room temperature and stirred overnight, then hydrochloric acid (4 M, 50 mL) is added and the resulting mixture is stirred for additional 2 h. The reaction mixture is extracted with ethyl acetate (50 mL, 3 times) and the collected organic phases are washed with 10% NaHCO3 solution and brine and volatiles evaporated under vacuum to yield 3-methylsulfanyl-phenyl)-methanol (1.20 g, content ca. 75%), which is directly used in the next step. Step B: A solution of 3-methylsulfanyl-phenyl)-methanol (1.20 g, content ca 75%) in dichloromethane (25 mL) and phosphorus tribromide (1 M in dichloromethane, 6.42 mL) is stirred for 3 h at room temperature. The reaction mixture is washed with NaHCO3 solution (10%, 10 mL, 2 times) and the remaining organic phase is dried (MgSO4) and volatiles are evaporated under reduced pressure to yield the title compound (1.35 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OC(C)=O)=O.[N+:27]([O-])([OH:29])=[O:28]>>[CH2:1]([O:8][C:9]1[C:17]([N+:27]([O-:29])=[O:28])=[C:13]([C:12]([O:18][CH3:19])=[CH:11][CH:10]=1)[C:14]([NH2:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(OCc2ccccc2)cc1C(N)=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-(benzyloxy)-2-methoxybenzamide (9, 0.365 g. 1.4 mmol) and Ac2O (1.2 mL) at 0° C. was added 70% HNO3 (0.14 mL, 2.1 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. Then 4.5 mL of 70% HNO3 precooled at −30° C. was added. The mixture was stirred at 0° C. for 1 h and was poured onto ice. The precipitate was collected, washed with water and dried in vacuo. Purification by silica gel chromatography eluting with 0-2.5% MeOH in CH2Cl2 afforded the title compound along with its regioisomer (0.34 g, 79%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.73 (br s, 1H), 7.41-7.30 (m, 5H), 7.11 (d, J=9.2 Hz, 1H), 7.00 (d, J=9.2 Hz, 1H), 6.84 (br s, 1H), 5.15 (s, 2H), 3.91 (s, 3H); ESI MS m/z 303 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:21][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(I)cc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 110.7 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(4-iodophenyl)-propanoic acid (5.0 g, 12.8 mmol) in DMF (50 mL) was treated with K2CO3 (2.2 g, 15.4 mmol). After stirring for 15 min, the solution was cooled to 0° C. and treated with iodomethane (1.0 mL, 15.4 mmol) After the addition was complete, the reaction mixture was stirred at room temperature for another 16 h, filtered and the resulting solid was washed with ethyl acetate (200 mL). The filtrate was washed successively with 5% aq HCl, sat. aq NaCl, dried over MgSO4 and concented. Purification by flash column chromatography (5% ethyl acetate in heptane) provided the desired product (5.74 g, 98%) as an oil. 1H NMR (CDCl3), δ 7.61 (d, J=9 Hz, 2 H), 7.74 (d, J=9, 2H), 4.97 (d, J=7 Hz, 1 H), 4.56 (m, 1 H), 3.73 (s, 3 H), 3.02 (ddd, J=7, 7, 12 Hz, 2 H), 1.47 (s, 9 H)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([CH:17]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CN(C)C=O>[Br:1][C:20]1[S:21][CH:22]=[CH:23][C:19]=1[CH2:18][CH:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCC(CCCCCCCC)Cc1ccsc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(CCCCCCCC)Cc1ccsc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A solution of N-bromosuccinimide (2.58 g, 14.5 mmol) in 100 mL of dimethylformamide (DMF) was added drop-wise into a solution of 3-(2-octyldodecyl)thiophene (4.90 g, 13.2 mmol) in 300 DMF at −20° C. The mixture was stirred overnight at room temperature. Next, the DMF was removed under vacuum and 100 mL water was added. The mixture was extracted with hexane three times and the organic layers were collected. After removal of hexane, a crude product was obtained and was purified by column to afford 5.60 g of the final product in the form of colorless oil (96%). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.18-7.17 (d, 1H, J=5.6 Hz), 6.76-6.75 (d, 1H, J=5.6 Hz), 2.50-2.48 (d, 2H, J=7.2 Hz), 1.64 (m, 1H), 1.30-1.25 (br, 32H), 0.90-0.87 (t, 6H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][CH2:17][C:18](=[O:25])[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:2]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:55][C:56]([CH3:58])=O>C(Cl)Cl.C(O)(=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][CH2:17][C:18]([N:19]2[CH2:20][CH2:21][N:22]([CH:56]([CH3:58])[CH3:55])[CH2:23][CH2:24]2)=[O:25])[N:2]=1
Reactant: CC(C)=O
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCNCC1)COC(=O)Nc1cc2ccccc2cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)CC[C@@H](COC(=O)Nc2cc3ccccc3cn2)N(C)C(=O)NCc2cccc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-oxo-5-(piperazin-1-yl)pentyl isoquinolin-3-ylcarbamate (610 mg, 1.07 mmol) in acetone (1 mL) and DCM (1 mL) was added acetic acid (4 drops, ˜0.2 mL). The reaction mixture was stirred at RT for 30 min. To this mixture was added solid NaBH(OAc)3 and the resulting mixture was stirred at RT for 1 h and concentrated. The residue was purified on RP-HPLC using a mixture of acetonitrle and water (0.1% HCOOH buffer). The fractions was collected, concentrated to dryness, and re-dissolved in EtOAc. The organic mixture was washed with Na2CO3, dried over Na2SO4, filtered, and concentrated to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(4-isopropylpiperazin-1-yl)-5-oxopentyl isoquinolin-3-ylcarbamate (540 mg, 82%) as white solid. LRMS (M+H+) m/z 613.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1cccc(O)c1
Product: OB(O)c1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce 5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.68 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 1H), 8.10 (d, 1H, J=3.9 Hz), 7.88-7.80 (m, 2H), 7.54 (d, 1H, J=7.2 Hz), 7.31 (t, 1H, J=7.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.98-6.93 (m, 2H), 6.35 (d, 1H, J=8.4 Hz); LCMS: purity: 96%; MS (m/e): 341(MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[CH:8](=[O:12])[CH2:9][CH2:10][CH3:11].[ClH:13]>C[Si](C)(C)N[Si](C)(C)C.O>[ClH:13].[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: CCCC=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: CCCC(O)P(=O)(O)CCCN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to room temperature and 14.8 g of freshly distilled n-butyraldehyde are added. An exothermic reaction ensues, the reaction temperature, rising to approximately 60° C. The reaction mixture is stirred for 1 hour at a temperature between 10° and 60°. After cooling to room temperature, the volatilematerials are removed in vacuo to yield a colourless oil. This oil is dissolved in water and stirred at room temperature for 1 hour and the aqueous layer is evaporated to dryness at 55°. A semi-solid residueis obtained which is dissolved in 50 ml of 2.0M aqueous hydrochloric acid and washed with dichloromethane, (3×100 ml), and ether (1×100 ml). After removal of the water the white solid is co-evaporated with water (10×50 ml), and then with 10×50 ml of absolute ethanol. Crystallisation of the residue form ethanol yields 3-aminopropyl(1-hydroxybutyl)phosphinic acid hydrochloride, m.p. 154°-160°. Treatment of the hydrochloride with propylene oxide/ethanol or passage through a DOWEX® 50 W×8 (14-40 mesh) ion-exchange column gives 3-aminopropyl(1-hydroxybutyl)phosphinic acid, m.p. 187°-188°, as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][NH:16][NH2:17]>>[NH2:10][C:6]1[NH:17][N:16]([CH2:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[Cl:12])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccccc1Cl
Product: Nc1cc(=O)n(Cc2ccccc2Cl)[nH]1
Yield: 40 %

Procedure:
35 g of β-amino-β-ethoxyacrylic acid ethyl ester and 32 g of 2-chlorobenzylhydrazine when reacted as described in Example 45 yield 17.5 g of the compound identified above as colorless crystals of melting point 153°. (Yield: 40% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21](NS(C)(=O)=O)=[O:22])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-:28].[Na+].O.Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:18][C:17]([CH3:20])([CH3:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:22])=[O:28])[CH:15]=3)[NH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CC(C)(C)c3cc(C(=O)NS(C)(=O)=O)ccc3N2)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(C2CC(C)(C)c3cc(C(=O)O)ccc3N2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 90.4 %

Procedure:
A mixture of N-[2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (1.0 g, 2.95 mmol), sodium hydroxide (0.59 g, 14.75 mmol), water (15 mL) in acetonitrile (30 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-methoxy-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.83 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=312.2.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([Cl:22])[C:6]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][CH:8]=2)[N:3]=1.[CH:23]([C:26]1[CH:30]=[CH:29][NH:28][N:27]=1)([CH3:25])[CH3:24].[H-].[Na+]>CN1C(=O)CCC1>[Cl:12][C:10]1[C:9]2[C:4](=[C:5]([Cl:22])[C:6]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:7][CH:8]=2)[N:3]=[C:2]([N:28]2[CH:29]=[CH:30][C:26]([CH:23]([CH3:25])[CH3:24])=[N:27]2)[CH:11]=1
Reactant: Clc1cc(Cl)c2ccc(OCCN3CCOCC3)c(Cl)c2n1
Reactant: CC(C)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)c1ccn(-c2cc(Cl)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)n1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To mixture of 2,4,8-trichloro-7-(2-morpholin-4-yl-ethoxy)-quinoline (0.34 g, 0.95 mmol) and 3-isopropyl-1H-pyrazole (0.63 g, 5.7 mmol) in NMP (3 ml) was added NaH (60% in mineral oil) (0.042 g, 1.05 mmol). The mixture was stirred at room temperature for over night and it monitored by LC-MS. The crude material was purified by pre-HPLC to afford 4,8-dichloro-2-(3-isopropyl-pyrazol-1-yl)-7-(2-morpholin-4-yl-ethoxy)-quinoline (0.204 g, 0.47 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[O:22]=[C:23]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[CH2:24][CH2:25][C:26](O)=[O:27].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:26](=[O:27])[CH2:25][CH2:24][C:23](=[O:22])[C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: O=C(O)CCC(=O)c1cccs1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCC(=O)c1cccs1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 55.8 %

Procedure:
(S)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl amine (0.200 gm, 0.00068 moles) was taken up in 1:1 THF-water mixture (20 ml). To this was added 4-oxo-4 (2-thienyl)butanoic acid (0.125 gm, 0.00068 moles) and HOBt (0.091 gm, 0.00068 moles). The resulting mixture was cooled to 0° C. and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.142 gm, 0.00074 moles) was added and the resulting mixture was allowed to warm to room temp and then stirred for 24 hr. The reaction mixture was concentrated, 15 ml of saturated sodium bicarbonate was added, stirred for 15 min and then extracted with ethyl acetate. The ethyl acetate layer was separated and the solvent evaporated off. The residue was chromatographed over silica gel (100-200 mesh, 20 gm). The column was eluted with mixture of ethyl acetate:hexane, and finally with ethyl acetate. The combined fractions were concentrated to give the title compound (0.175 gm, 56%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:10][CH3:11])[S:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:12](O)=O>O>[CH3:11][S:10][C:4]1[S:5][C:6]2[C:7](=[O:8])[N:9]=[CH:12][NH:1][C:2]=2[N:3]=1
Reactant: CSc1nc(N)c(C(N)=O)s1
Reactant: O=CO
Solvent: O
Product: CSc1nc2[nH]cnc(=O)c2s1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 4-amino-2-(methylthio)thiazole-5-carboxamide (3.37 g, 17.8 mmol) in formic acid (10 mL) was stirred at reflux for 12 hours. After cooled to ambient temperature, the reaction mixture was diluted with water (30 mL) and the precipitate was collected by filtration. The resulting solid was further washed with water and dried in vacuo. The product was obtained as a yellow solid (2.978 g, 84%). 1H NMR (300 MHz, d6-DMSO) δ 12.83 (br, 1H), 8.26 (s, 1H), 2.80 (s, 3H); LC-MS: 200 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:18]([O-:20])=[O:19])[C:13]=1[NH:14][C:15](=[O:17])[CH3:16])[C:8]([OH:10])=[O:9])(=O)C.Cl>[OH-].[Na+].O>[C:15]([NH:14][C:13]1[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[OH:4])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(OC(C)=O)cc(C(=O)O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1c(O)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
Compound 104 (0.850 g, 3.54 mmol) was dissolved in 0.1N NaOH (80 mL), and the mixture was stirred at room temperature for 4 hours. This was acidified with concentrated HCl (2 mL), diluted with water (20 mL), and extracted with ethyl acetate (3×60 mL). The combined extracts were dried (Na2SO4) and concentrated on a rotary evaporator to give crystalline 105 (0.712 g, 98.4% yield): mp 256°-259 ° C (methanol).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12]([N:14]1[CH2:19][CH2:18][NH:17][C:16]([CH3:21])([CH3:20])[C:15]1=O)=O)(C)(C)C>C1COCC1>[CH3:12][N:14]1[CH2:19][CH2:18][NH:17][C:16]([CH3:21])([CH3:20])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCNC(C)(C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
LiAlH4 (1M in THF, 32.5 mL, 32.5 mmol, 1.5 equiv) was added to a solution of 3,3-dimethyl-2-oxo-piperazine-1-carboxylic acid tert-butyl ester (Step 114.3) (4.95 g, 21.7 mmol) in THF (100 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 3 h at 50° C., cooled to 0° C., quenched by addition of acetone and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 2 g of the title compound as a yellow oil. Title compound: ESI-MS: 129.1.