Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2(OC)[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[NH:13]2)=[O:11])=[CH:4][CH:3]=1.P(Br)(Br)Br.C(=O)([O-])[OH:33].[Na+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:33])[NH:14][N:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: COC1(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)C=CC=[N+]([O-])N1
Agent: BrP(Br)Br
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)[nH]n1)c1ccc(Br)cc1

Procedure:
A mixture of (R)-6-(3-(3-(4-bromophenyl)-3-o-tolylpropanoyl)-3-methoxypyridazine 1-oxide (679 mg, 1.59 mmol) and phosphorous tribromide (2.58 g, 9.53 mmol) in ethyl acetate (15 mL) was heated at reflux for 30 min, then after cooling poured onto ice water, neutralized with sat. aq. sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. After chromatography (SiO2; heptane-ethyl acetate gradient) the title compound was obtained (318 mg, 50%). White semisolid, MS: 397.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>C1C=CC=CC=1.O>[C:28]([O:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: OCc1ccc(OCCCc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(OCCCc2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
A mixture of 2.0 g (0.007 mole) of 4-[3-(4-chlorophenyl)propoxy)-phenylmethanol and 4.0 g triethylamine is added to 3.6 g (0.02 mole) of hydrochloride of nicotinoyl chloride in 50 ml of anhydrous benzene with stirring and the mixture is refluxed for 4 hrs. After cooling, water is added to the reaction mixture. The product is extracted with benzene and the extract is washed with water and dried over sodiun sulfate. Benzene is removed, the residual solid is recrystallized from ethanol to give a title compound in yield of 1.8 g (67.3%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46]([N:48]([CH2:50][C:51](O)=[O:52])[CH3:49])=[O:47])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:41]([O:45][C:46](=[O:47])[N:48]([CH2:50][C:51](=[O:52])[NH:1][CH2:2][C@H:3]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2)[CH3:31])[CH3:49])([CH3:44])([CH3:42])[CH3:43]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CNC(=O)CN(C)C(=O)OC(C)(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 18 h

Procedure:
5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials, 868 mg) was stirred in DCM (40 ml) with DIPEA (1 ml). N-(tert-butoxycarbonyl)sarcosine (400 mg) and HATU (800 mg) were added and mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (0-10%). Evaporation of the appropriate fractions gave the title compound as a froth (0.50 g); NMR spectrum (DMSO-d6 @ 373k) 1.10 (s, 6H), 1.20 (s, 3H), 1.40-1.42 (d, 3H), 2.72 (s, 3H), 3.40-3.60 (d, 1H, (masked by H2O), 3.60-3.75 (q, 2H), 3.75-3.80 (d, 1H), 4.90-5.00 (bs, 1H), 5.30 (s, 2H), 7.28-7.34 (q, 2H), 7.34-7.40 (m, 1H), 7.42-7.46 (d, 1H), 7.50-7.62 (m, 2H), 7.85-7.91 (dt, 1H), 7.91-7.99 (m, 2H), 8.24-8.34 (bs, 1H), 8.57-8.62 (d, 1H), 8.75 (s, 1H), 10.60-10.70 (bs, 1H); Mass spectrum MH+ 607.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([F:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][N:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[F:33][C:21]1[CH:20]=[C:19]([CH2:18][C:15]2[C:16](=[O:17])[N:11]([CH:8]3[CH2:7][CH2:6][CH:5]([OH:4])[CH2:10][CH2:9]3)[C:12]3[N:13]([N:37]=[CH:38][N:39]=3)[C:14]=2[CH2:34][CH2:35][CH3:36])[CH:24]=[CH:23][C:22]=1[C:25]1[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n(C2CCC(O)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile (1.2 g), 3N hydrochloric acid (50 mL) and tetrahydrofuran (50 mL) was stirred at 80° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), sodium borohydride (0.17 g) was added, and the mixture was stirred at room temperature for 1 hr. After evaporation of the solvent under reduced pressure, the residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.95 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.[H][H]>[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:12][C:9](=[O:10])[CH2:8]2
Reactant: O=C(O)Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]
Product: O=C1Cc2cc(F)ccc2N1

Procedure:
A mixture of 24 g. of 5-fluoro-2-nitro-phenylacetic acid, 2.0 g. of platinum oxide (PtO2) and 250 ml. of glacial acid is hydrogenated at room temperature and 50 p.s.i. until the theoretical amount of hydrogen is taken up. The resulting mixture is filtered and the solvent evaporated off in vacuo. The residue is triturated with water and the resulting precipitate recrystallized from methylene chloride/diethyl ether to obtain 5-fluoro-oxindole, m.p. 131°-133° C.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]#[N:15])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2.[OH-].[Na+].C([OH:36])C.O>C(Cl)Cl>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]([C:14]([NH2:15])=[O:36])=[N:8][C:7]2[N:6]=[C:5]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:4][C:3]1=2
Reactant: CCCn1c(C#N)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCn1c(C(N)=O)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
A mixture of 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carbonitrile (40 mg, 0.0934 mmol), NaOH (6 mg, 0.140 mmol) and Ethanol:water (3:1) (2 ml) were stirred at 50° C. for 18 hours. Reaction mixture was cooled and organic volatiles were evaporated and the residue obtained was dissolved in DCM (10 ml) and washed with brine (10 ml). Organic layer was dried over Na2SO4 and evaporated to obtain pure 6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purine-2-carboxylic acid amide (32 mg, 78%) as an off white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([S:13](=[O:17])(=[O:16])[C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.Cl([O-])=[O:19].[Na+]>S(=O)(=O)(O)O.O>[OH:19][C:15]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]2[C:14]=1[S:13](=[O:17])(=[O:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[N:6]=2
Reactant: [O-][Cl+][O-]
Reactant: O=S1(=O)c2ccccc2Nc2ccc(O)cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1C=CC2=Nc3ccccc3S(=O)(=O)C2=C1O
Reaction time: 0.25 h
Yield: 94.6 %

Procedure:
To a suspension of 3-hydroxy-10H-phenothiazine-5,5-dioxide (1.75 g, 7 mmoles) in 2% aqueous sulfuric acid (25 ml) there was added, at room temperature, a solution of 80% sodium chlorite (3.17 g, 28 mmoles) in water (25 ml). The mixture was stirred for 15 minutes, then the red-orange precipitate was filtered to afford crude product (1.73 g). Purification was achieved by crystallization from DMF-methanol, m.p. 266° (dec.).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([O:19][C:20]1[C:21](=[O:29])[CH:22]=[C:23](C(O)=O)O[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(O)=O>O>[CH2:12]([O:19][C:20]1[C:21](=[O:29])[CH:22]=[CH:23][N:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: CCCCc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1ccc(-n2ccc(=O)c(OCc3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-butyl aniline (0.6 g, 4.1 mmol) and 5˜(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (1.0 g, 4.1 mmol) in a 1:1 mixture of AcOH:water (4 mL) was heated in a sealed reaction vessel at 120° C. for 72 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with 10 mL 10% aq. NaOH, and extracted with EtOAc (3×10 mL). The organic fractions were pooled, dried (Na2SO4), and concentrated under reduced pressure to provide 3-(benzyloxy)-1-(4-butylphenyl)pyridin-4(1H)-one, which was used in the subsequent step without further purification. LC/MS (M+H)+ 334.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:19]1([CH2:22][C:23]2[C:28]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)=O)[N:30]=3)=[CH:27][N:26]=[C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:24]=2)[CH2:21][CH2:20]1>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:31]2[N:30]=[C:29]([C:28]3[C:23]([CH2:22][CH:19]4[CH2:21][CH2:20]4)=[N:24][C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])=[N:26][CH:27]=3)[CH:34]=[CH:33][N:32]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccnc(Cl)c3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 minutes. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 hour. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (29 mg, 49%).
Reaction SMILES: C(OC([N:6]([CH2:13][CH:14]([OH:24])[CH2:15][P:16](=[O:23])([O:20]CC)[O:17]CC)[O:7]C(OCC)=O)=O)C.C[Si](C)(C)Br.C.C1OC1C>C(Cl)Cl.O.Cl.CO>[OH:24][CH:14]([CH2:13][NH:6][OH:7])[CH2:15][P:16](=[O:17])([OH:23])[OH:20]
Reactant: CCOC(=O)ON(CC(O)CP(=O)(OCC)OCC)C(=O)OCC
Agent: CC1CO1
Agent: C[Si](C)(C)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=P(O)(O)CC(O)CNO
Reaction time: 2.5 h
Yield: 53.4 %

Procedure:
To a solution of diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2-hydroxypropylphosphonate (24.0 g.) in methylene chloride (50 ml.) was added dropwise trimethylbromosilane (41 ml.) under ice-cooling, whereafter the mixture was stirred for half an hour at the same temperature and then for additional 2.5 hours at ambient temperature. After the reaction was completed, the chloroform and the excess of the trimethylbromosilane was distilled off from the reaction mixture under reduced pressure to give a residue, which was dissolved in water (125 ml.) and stirred for an hour at ambient temperature. This aqueous solution was washed three times with chloroform (each 30 ml. portion) and evaporated to dryness under reduced pressure to give a residue, which was dissolved in 1 N hydrochloric acid (240 ml.) and heated to reflux for 15 hours. The resultant aqueous solution was evaporated to dryness under reduced pressure to give a residue, which was dissolved in water (60 ml.), decolorized with activated charcoal (500 mg.) and evaporated to dryness under reduced pressure. The residue thus obtained was dissolved in a mixture of water (20 ml.) and methanol (40 ml.), and adjusted to pH 3-4 with propylene oxide (about 25 ml.) to precipitate oily materials. Furthermore, to this solution was added ethanol (80 ml.) and allowed to stand for a while in order to precipitate said materials completely, and these materials were collected by decantation and dissolved in water (20 ml.). The insoluble materials were removed by filtration, and to the filtrate was added methanol (35 ml.) at 50°-60° C. The resultant solution was allowed to stand for 3.5 hours at ambient temperature, and precipitating crystals were collected by filtration, washed twice with methanol (10 ml.) and dried on phosphorus pentoxide to give 2-hydroxy-3-(N-hydroxyamino)propylphosphonic acid (5.9 g.).
Reaction SMILES: [CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[NH:16][C:15]1=[O:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:29]>CC#N.C1COCC1>[CH:1]([N:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:17](=[O:26])[N:16]([CH3:29])[C:15]1=[O:27])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: O=c1[nH]c(=O)n(C(c2ccccc2)c2ccccc2)cc1-c1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1c(=O)c(-c2ccccc2)cn(C(c2ccccc2)c2ccccc2)c1=O
Yield: 43 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 16 (Step 1) starting from 1-benzhydryl-5-phenyl-pyrimidine-2,4-dione (prepared as in Example 14, Step 2) (0.37 g, 1.01 mmol); a 1:1 mixture of was dry MeCN/THF and iodomethane were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 80:20) to afford the title compound (0.16 g, 43%) as a light-red solid. 1H NMR (400 MHz, CDCl3): δ 3.46 (s, 3H), 7.19-7.24 (m, 6H), 7.28-7.43 (m, 11H). MS (ESI) m/z: 369 [m-H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](Cl)=[O:30]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:29]([C:25]5[S:24][CH:28]=[CH:27][CH:26]=5)=[O:30])[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Reactant: O=C(Cl)c1cccs1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1cccs1)N1CCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C1
Reaction time: 8 h

Procedure:
To a mixture of 0.40 g (1.55 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline and 2 ml of dimethylformamide at 0° C. is added 0.23 g (1.55 mmol) of 2-thiophencarbonylchloride. The reaction mixture solution is allowed to stir overnight while slowly reaching room temperature. The reaction mixture is then diluted with water producing a tan precipitate which is collected by filtration, washed with water and dried to yield 0.282 (50%) of the title compound as a tan solid: m.p.>250° C.; IR (KBr) 3420, 1640, 1440 cm-1 ; NMR (DMSO-d6) δ14.1 (s, 1H), 9.6 (s, 1H), 8.6 (d, 1H), 8.3 (s, 1H), 8.0 (d, 1H), 7.8 (d, 1H), 7.6 (s, 1H), 7.2 (d, 1H), 5.0 (s, 2H), 4.0 (t, 2H), 3.1 (m, 2H); m/e 368 (M+H).
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]([CH2:21][C:22]([C:24]1([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25]1)=O)[C@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14])=[O:11])(OCC)=O)C.C(O[K])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27]([C:24]1([C:22]2[CH2:21][N:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:14])[C:10](=[O:11])[CH:9]=2)[CH2:26][CH2:25]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Agent: CC(C)(C)O[K]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C2=CC(=O)N([C@@H](C)c3ccccc3)C2)CC1
Yield: 73.2 %

Procedure:
After dissolving ethyl 1-[2-[N-(diethylphosphonoacetyl)-N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (25.0 g, 55.2 mmol) in toluene (250 ml), tert-butoxypotassium (7.40 g, 66.2 mmol) was added gradually while stirring and cooling with ice. After stirring the reaction solution for 15 minutes at room temperature, a 10% aqueous citric acid solution (250 ml) and ethyl acetate (250 ml) were added thereto, and after performing an extraction operation, the organic layer was separated. The aqueous layer was then subject to extraction with ethyl acetate (250 ml), and after washing the combined organic layer with saturated sodium bicarbonate water (250 ml) and saturated saline solution (250 ml) in that order, the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 12.1 g (73%) of the title compound was obtained as a orange syrup from an n-hexane:ethyl acetate=2:1 to 1:2 eluate. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:44][C:41]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:35]([C:36](=[O:37])[NH:38][CH3:39])[CH:40]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A 25 mL round-bottom flask was charged with intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid, (0.991 g, 3.0 mmol), intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (1.185 g, 4.0 mmol), 4-dimethylaminopyridine (DMAP, 1.1 g, 9.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.722 g, 4.5 mmol). Dimethylformamide (20 mL) was added and the mixture stirred for 1 h at ambient temperature. After this, the reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (3×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered, concentrated and purified by flash chromatography (SiO2), eluting with hexanes/ethyl acetate (1:1 to 1:3) followed by ethyl acetate, to afford the title compound as an off-white solid (1.48 g, 100% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 8.49 (1H, t, J=6.1 Hz), 7.48-7.46 (2H, m), 7.43 (1H, dd, J=8.5, 5.5 Hz), 7.31-7.27 (3H, m), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.05 (1H, td, J=8.2, 2.7 Hz), 6.52 (1H, br s), 5.26 (2H, s), 4.53 (2H, d, J=6.4 Hz), 4.01 (2H, t, J=4.9 Hz), 3.96 (2H, t, J=4.9 Hz), 2.97 (3H, d, J=4.9 Hz), 1.62 (6H, s). HRMS (M+H) calcd for C26H28FN4O5: 495.2044; found: 495.2032.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:22])=O>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([Cl:22])=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Temperature: 79 °C
Yield: 98.3 %

Procedure:
59.8 g (233.4 mmol) of 4′-acetoxybiphenyl-4-carboxylic acid and 278 g (2.33 mol) of purified thionyl chloride were placed in a reactor and refluxed under heat (79° C.) for 4 hours. Thionyl chloride was distilled off under atmospheric pressure, 150 ml of toluene was added, and toluene and thionyl chloride were distilled off under reduced pressure, to give 63 g of an end compound (yield498%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[S:9][C:8](=O)[NH:7][C:6]=2[CH:11]=1.[N:13]([O-])=O.[Na+].[OH-:17].[K+]>Cl>[F:12][C:3]1[C:2]([NH:1][NH2:13])=[CH:11][C:6]2[NH:7][CH2:8][S:9](=[O:17])[C:5]=2[CH:4]=1
Reactant: O=N[O-]
Reactant: Nc1cc2[nH]c(=O)sc2cc1F
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: NNc1cc2c(cc1F)S(=O)CN2
Reaction time: 0.5 h

Procedure:
A suspension of 5-amino-6-fluoro-2(3H)-benzothiazolone (12.98 g) in conc. hydrochloric acid (70 g) was cooled to 0° to 5° C., and a saturated aqueous solution of sodium nitrite (5.08 g) was dropwise added thereto at 0° to 5° C., followed by stirring at the same temperature for 30 minutes. The resultant mixture was cooled to -20° C., and a solution of stannous chloride (28.06 g) in conc. hydrochloric acid (30 g) was added thereto all at once, followed by stirring at 0° C. for 2 hours. The reaction mixture was neutralized with potassium hydroxide, a colloidal substance originated from stannous chloride was removed by celite and the resultant solution was extracted with ethyl acetate. The extract was washed with water, fried over magnesium sulfate and concentrated by give 6-fluoro-(3H)-benzo-thiazolon-5-ylhydrazine (6 60 g).
Reaction SMILES: [NH2:1]C(O)C.Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:16]([OH:18])[CH3:17]>>[CH2:6]([NH:1][CH2:17][CH2:16][OH:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCBr
Reactant: CCO
Reactant: CC(N)O
Product: CCCCCCCCCCNCCO

Procedure:
A solution of aminoethanol (30.5 g, 500 mmol, 30.1 mL) and 1-bromodecane (27.65 g, 125 mmol, 26 mL) in ethanol was stirred at 65 ° C. for 4 hr. The solvent was removed under reduced pressure. The residue was diluted with EtOAc (800 mL) and the organic solution was washed with H2O (2×200 mL); saturated aqueous NaHCO3 (200 mL) and saturated brine (200 mL). The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude product, 2-(decylamino)ethanol, was used without further purification.