Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][O:9][P:6]([O:7][CH2:8]1)[O:5][CH2:4]2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:6]12[O:9][CH2:10][C:3]([CH2:2][O:1][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH2:8][O:7]1)[CH2:4][O:5]2
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC12COP(OC1)OC2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCC12COP(OC1)OC2)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
16.4 g (0.1 mol) of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane are dissolved in 150 ml of toluene by warming. 19.6 g (0.1 mol) of benzoyl chloride are added dropwise at room temperature, followed by 10.1 g (0.1 mol) of triethylamine. The temperature is kept at 30 C by means of an ice bath. After the dropwise addition is complete, the mixture is stirred for 2 hours at 60°C and is then heated to the boil for a short time and filtered while hot from triethylamine hydrochloride. The filtrate is cooled, whereupon the product is precipitated. After filtering and drying, benzoic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4 -yl-methyl ester (Stabiliser No. 1) of melting point 160°C is obtained. After recrystallisation from ethanol or isopropanol the product forms long, snow-white needles. If in this example, the benzoyl chloride is replaced by an equivalent quantity of one of the substituted benzoic acid chlorides in Table 1 below, an otherwise identical procedure gives benzoic acid 1-phospha-2,6,7-trioxabicyclo[2,2,2]oct-4-yl methyl esters substituted at the nucleus, the melting points of which are shown.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:23][N+:24]([O-])=O)[CH2:10][P:11]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[NH2:24][CH2:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][P:11]([CH:16]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])(=[O:15])[O:12][CH2:13][CH3:14]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(OC)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC

Procedure:
A solution of 6.6 g of ethyl 2-(4-methoxyphenyl)-3-nitropropyl-(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methoxyphenyl)propyl-(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.5 ppm (CDCl3).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:23])([F:25])[F:24])[O:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), ethanamine-HCl (9.95 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.3 min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.063 mmol, 77% yield): LCMS=458.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.11 (2 H, d, J=8.58 Hz), 7.51-7.72 (7 H, m), 5.09 (1 H, s), 3.24-3.30 (2 H, m), 1.14 (3 H, t, J=7.15 Hz); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[CH3:17][CH2:18][Mg+].[Br-]>>[CH2:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)[CH3:18]
Reactant: CC[Mg+]
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Agent: [Br-]
Product: CCC1=CCC(C)(C)c2cc(C)c(OC)cc21
Yield: 62.3 %

Procedure:
Following General Procedure A, 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 0.5 g, 2.3 mmol) was reacted with a solution of 3 M EtMgBr (2.3 mL, 6.9 mmol), and the crude product was purified by flash chromatography (hexane:ethyl acetate=4:1) to give 0.33 g (63%) of the title compound as a clear oil. PNMR (300 MHz, CDCl3) δ 1.32 (t,3 H, J=6.3 Hz), 1.38 (s, 6 H), 2.32 (d, 2 H, J=4.5 Hz), 2.42 (s, 3 H), 2.65 (m, 2 H), 3.98 (s, 3 H), 5.88 (t, 1 H, J=2.5 Hz), 6.96 (s, 1 H), 7.28 (s, 1 H).
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][Cl:33]>CN(C=O)C>[Cl:33][CH2:32][CH2:31][O:23][C:16]1[C:15]2[C:14]3[C:22]4=[C:10]([O:9][CH2:8][CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:21]4[C:20]=2[CH:19]=[CH:18][CH:17]=1)[CH:11]=[CH:12][CH:13]=3
Reactant: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 85 °C
Yield: 93.8 %

Procedure:
To a mixture of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (3.0 g 9.96 mmol) and potassium carbonate (6.9 g, 50 mmol) in dry DMF (70 mL) is added 1-bromo-2-chloroethane (4.0 mL, 50 mmol). The mixture is heated to 85° C. for 8.25 h. The mixture is then partitioned between water and Et2O. The organic layer is separated and washed three times with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (200 mL silica) using CH2C2/hexanes (1/1) as eluent gave 3.4 g (94%) of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole.
Reaction SMILES: O(CC(C)C)[C:2]([S-:4])=[S:3].[K+].Cl[C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=1[NH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:18][C:14]1[C:12]2[N:13]=[C:2]([SH:4])[S:3][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)COC(=S)[S-]
Reactant: Cc1cccc(Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2sc(S)nc12
Reaction time: 26 h
Yield: 94.9 %

Procedure:
A solution of 250 g of potassium isobutyl xanthate (about 90% pure) in 400 ml of dimethylformamide is added dropwise to a mixture of 141.5 g of 2-chloro-6-methylaniline and 276 g of potassium carbonate in 1 liter of dimethylformamide at 150° C. in the course of one hour, under a nitrogen atmosphere. The reaction mixture is stirred for about a further 26 hours, whilst cooling intensively. The batch is cooled, freed from salt and then concentrated to dryness. The residue is taken up in 400 ml of water and the mixture is acidified. The 4-methyl-2-mercaptobenzothiazole which precipitates is filtered off, washed with water and dried. 172 g (95% of theory) of 4-methyl-2-mercaptobenzothiazole of melting point 188°-190° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:36](=[O:35])[CH2:37][OH:38])[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Reactant: CC(=O)OCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)CO)sc5c4)c3)c2)CC1
Yield: 26.4 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (310 mg, 726 μmol) produced in Example A15(iii), pyridine (10 mL), 2-chloro-2-oxoethyl acetate (269 mg, 1.97 mmol) and N,N-dimethylpyridine-4-amine (62.1 mg, 508 μmol) as starting materials, and in the same manner as in Example A14, the title compound (93 mg, 26%) was obtained as colorless crystals. In this Example, the purification operation was performed using silica gel column chromatography (hexane/ethyl acetate=5/95→20/80).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH:27]1([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]3[S:38][C:39]([C:43]([OH:45])=O)=[C:40]([CH3:42])[N:41]=3)[C:32]2=[O:46])[CH2:29][CH2:28]1.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=1>>[CH:27]1([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]3[S:38][C:39]([C:43]([NH:54][CH2:53][C:49]4[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=4)=[O:45])=[C:40]([CH3:42])[N:41]=3)[C:32]2=[O:46])[CH2:28][CH2:29]1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 22 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxotetrahydro pyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 22% yield: mp 142-145° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 8.52-8.51 (m, 1H), 7.68-7.65 (m, 1H), 7.28-7.23 (m, 1H), 6.07 (m, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.15 (t, J=5.9 Hz, 2H), 3.48 (t, J=5.9 Hz, 2H), 3.31 (d, J=7.0 Hz, 2H), 2.61 (s, 3H), 2.16-2.09 (m, 2H), 1.05-0.98 (m, 1H), 0.55-0.49 (m, 2H), 0.28-0.23 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.0, 159.2, 152.9, 152.7, 149.0, 148.6, 135.6, 133.9, 123.6, 117.6, 52.8, 45.6, 45.5, 41.2, 21.3, 17.3, 9.3, 3.4; MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].[NH:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].C(N)CN.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.C1(C)C=CC=CC=1>[NH2:4][C:3]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:2]=1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: O=C1CCCN1
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: Cc1ccccc1
Product: Nc1cc(C(F)(F)F)ccc1N1CCCC1=O
Temperature: 80 °C

Procedure:
A resealable tube was charged with 2-bromo-5-(trifluoromethyl)aniline (1.00 g, 4.16 mmol), 2-pyrrolidinone (0.425 g, 5.00 mmol), N,N′-ethylene diamine (0.037 g, 0.42 mmol), potassium carbonate (1.15 g, 8.32 mmol), copper iodide (0.80 mg, 0.42 mmol) and toluene (1.0 mL). The tube was sealed and the mixture was heated at 80° C. for 24 h. The resulting mixture was partitioned between ethyl acetate and water. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford 1-(2-amino-4-(trifluoromethyl)phenyl)pyrrolidin-2-one as a gray solid. MS m/z=245 [M+H]+. Calc'd for C11H11F3N2O: 244.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH:6][C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:13]([O:15]CC)=O)[CH:3]=[N:2]1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:15]=[C:13]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[NH:6][C:4]2[CH:5]=[N:1][NH:2][C:3]1=2
Reactant: CCOC(=O)C1=C(Nc2cn[nH]c2)CCCC1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: O=c1c2c([nH]c3cn[nH]c13)CCCC2
Temperature: 25 °C
Yield: 91.9 %

Procedure:
Ethyl 2-(pyrazol-4-ylamino)cyclohexene-1-carboxylate (8.5 g, 0.036 mole) was added rapidly to refluxing Dowtherm A (250 ml) under nitrogen and the mixture heated under reflux for a further 15 minutes, before allowing to cool to room temperature. The mixture was diluted with 60°-80° petroleum ether (200 ml) and the solid then filtered off, washed well with petroleum ether and then ethanol, before drying under vacuum to give the title compound as a white solid (6.26 g, 92%), m.p. >325° C. Found: C, 63.20; H, 5.85; N, 22.20% C10H11N3O requires C, 63.50; H, 5.85; N, 22.20%
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[Na].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([O:18][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Nc1nc(N)nc(Cl)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1nc(N)nc(OCc2ccccc2)n1
Temperature: 130 °C

Procedure:
2,4-Diamino-6-chloro-s-triazine (2.25 g, 15.0 mmol) was added to a solution of sodium (0.43 g, 18.8 mmol) in benzyl alcohol (30 mL) under argon. The suspension was heated in a 130° C. oil bath for 3.5 h. The excess benzyl alcohol was removed under vacuum and the resulting solid was collected with the aid of benzene, and washed with water (100 mL): yield, 1.83 g (56%); mp 184-185° C. (lit. 186-188° C.; Wakabayashi et al., Nippon Dojo-Hiryogaku Zasshi, 41, 193-200 (1970)); UV (pH 1) λmax 233 nm (sh) (ε=0.589×104); (pH 6.9) 238 (sh) (0.111×104); (pH 13) 240 (sh) (0.073×104); 1H NMR δ 5.25 (s, 2H, ArCH2), 6.63 (s, 4H, NH2, exchange with D2O), 7.30-7.42 (m, 5H, ArH); MS (EI) calcd. m/z for C10H11N5O 217.0963, found 217.0955.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][CH3:19]>C(Cl)Cl.O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([N:18]([CH3:19])[CH3:17])=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC
Reactant: COc1cc(C(C)(C)C)ccc1CC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C(C)(C)C)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Step B was dissolved in 20 mL CH2Cl2 and 5.0 mL of a 2 M solution of dimethylamine in tetrahydrofuran was added. The reaction mixture was stirred overnight at room temperature, and then concentrated in vacuo. The residue was partitioned between 50 mL EtOAc, 20 mL water and 10 mL of 5 N sodium hydroxide. The aqueous layer was separated and re extracted with EtOAc, then the organic layers were combined, dried Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:9])=[O:7])=[CH:4][N:3]=1.[SH2:19].[Na]>CN(C=O)C.C(OCC)(=O)C>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([SH:19])=[N:3][CH:4]=2)=[CH:11][CH:12]=1
Reactant: CN(C(=O)c1ccc(Cl)nc1)c1ccc(F)cc1
Reactant: S
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(S)nc1)c1ccc(F)cc1
Yield: 71.9 %

Procedure:
6-Chloro-N-(4-fluoro-phenyl)-N-methyl-nicotinamide (396 mg, 1.5 mmol) was dissolved in anhydrous DMF (6 mL) under nitrogen. Sodium hydrogen sulfide (181 mg, 1.5 mmol) was added and the solution was refluxed for 70 minutes. After cooling, the solution was diluted with ethyl acetate and washed with water. The water was washed with ethyl acetate, and the combined aqueous layers were acidified with 1 N HCl and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, saturated sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and dried in vacu to yield N-(4-Fluoro-phenyl)-6-mercapto-N-methyl-nicotinamide as a yellow solid (283 mg, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:51])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]C)=[O:48]>>[C:47]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:51])=[O:17])([OH:49])=[O:48]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)CCCCCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 184, the title compound was prepared in 47% overall yield by alkylation of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one with 2-[(9-methoxy-9-oxononyl)oxy]-6-[6-[(methylsulfonyl)oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example followed by saponification. The diacid product was a colorless solid, mp 63°-65° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1Br)([CH3:3])[CH3:2].O1CCCC1.C([Li])CCC.[B:23](OCC)([O:27]CC)[O:24]CC>CCCCCC>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH3:12])[CH:8]=[CH:9][C:10]=1[B:23]([OH:27])[OH:24])([CH3:3])[CH3:2]
Reactant: CCOB(OCC)OCC
Reactant: Cc1ccc(Br)c(OC(C)C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(B(O)O)c(OC(C)C)c1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To a 125 mL 3N round-bottomed flask equipped with N2 inlet and septum were added 3.59 g (15.7 mmol) 3-isopropoxy-4-bromotoluene and 30 mL dry tetrahydrofuran. The solution was cooled to −70° C. and 7.5 mL (18.8 mmol) of a 2.5 M solution of butyl lithium in hexane was added over 5 minutes, and the solution stirred 5 minutes at −70° C. Then 3.2 mL (18.8 mmol) triethyl borate was added, followed by stirring for 5 minutes at −70° C. and then stirring at room temperature for 24 hours. The reaction was quenched with 1 N aqueous hydrochloric acid and extracted into ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated. The residue was triturated with hexane to a white solid, 1.7 g (56%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:12].[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2ccc(F)cc12
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(NC1CCN(CCc2ccccc2)CC1)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C

Procedure:
To a solution of 0.6 g of 5-fluoro-N-(4-piperidyl)indole-3-carboxamide in a mixture of 50 ml of toluene and 10 ml of dimethylformamide were added 0.43 g of 2-phenylethylbromide and 1 g of potassium carbonate, and the whole mixture was stirred while heating and refluxing for 7 hours. After cooling, to the reaction mixture was added 50 ml of ice-cold water and stirred for 1 hour. The precipitated crystals were filtered, and washed with water and ethyl acetate. An organic layer was separated from the filtrate, dried over magnesium sufate and concentrated under reduced pressure. The residue was treated with a small amount of ethyl acetate to crystallize, and the crystals were filtered and combined with the crystals obtained as above. All of the crystals were recrystallized from methanol to give 5-fluoro-N-[1-(2-phenylethyl)-4-piperidyl]indole-3-carboxamide, melting at 238°-240° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[OH:26].[C:27]([O:32]C)(=[O:31])[C@@H:28]([CH3:30])O.BrBr>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:4][C:3]=1[O:26][C@@H:28]([CH3:30])[C:27]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](C)O
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br
Agent: BrBr
Product: C[C@H](Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)ccc1Br)C(=O)O

Procedure:
Prepared from of 2-bromo-5-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenol (Example 68) and commercially available (R)-lactic acid, methyl ester. White solid: mp 132-134° C.: MS (+EI): [M+], 2 bromine isotope pattern, 554, 556, 558; Anal. Calc. for C25H16Br2O3S: C, 53.98, H, 2.90, N, 0.00. Found: C,52.97, H, 2.98, N, 0.04.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>CS(C)=O>[CH2:31]([O:20][C:3]1[C:4]2=[C:13]3[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]2)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]3=[CH:14][C:2]=1[F:1])[CH3:32]
Reactant: CC1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C

Procedure:
A solution of 1.0 g of 6,7-dihydro-9-fluoro-8-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 1.4 g of potassium carbonate and 2.0 ml of diethyl sulfate in 15 ml of dimethyl sulfoxide was heated at its reflux temperature for sixteen hours. The solution was then evaporated to dryness by heating on a steam bath under a stream of nitrogen. Fifty ml of 1% aqueous sodium hydroxide solution was added to the resulting residue. The mixture was heated on a steam bath for one hour, acidified with concentrated hydrochloric acid and cooled. The solid was separated by filtration and recrystallized from aqueous ethanol to provide 6,7-dihydro-8-ethoxy-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 208°-210° C. (dec.). Analysis: Calculated for C16H16FNO4 : %C,63.0;%H,5.3;%N, 4.6; Found: %C,62.9;%H,5.3;%N,4.6.
Reaction SMILES: [C:1]([CH2:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)#[N:2].O.[NH2:20][NH2:21]>CCO>[NH2:2][C:1]1[NH:21][N:20]=[C:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:3]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)CC1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N)[nH]n2)CC1
Temperature: 80 °C

Procedure:
A 5 mL conical reaction vial was charged with tert-butyl 4-(2-cyanoacetyl)piperidine-1-carboxylate (348 mg, 1.379 mmol), hydrazine monohydrate (329.4 μL, 6.896 mmol) and EtOH (4 mL). The reaction vessel was sealed and heated to 80° C. for 20 hours. The volatiles were removed to afford tert-butyl 4-(5-amino-1H-pyrazol-3-yl)piperidine-1-carboxylate as a foam (367 mg. 99%).