Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1.N([O-])=O.[Na+].C1C=CN=CC=1.[FH:35].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:35][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1
Reactant: F
Reactant: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(F)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Temperature: 0 °C
Yield: 57.7 %

Procedure:
3-Ethyl 5-methyl 2-amino-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (5.0 g, 15.23 mmol) (Example 1, Step C) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Sodium nitrite (5.25 g, 76.15 mmol) was added followed by HF-Pyridine (4.0 mL, 160 mmol). The reaction was stirred at ambient temperature until complete by LCMS. Ethyl acetate and sodium bicarbonate solution was added, the precipitated solid was filtered, and the filtrate was extracted with ethyl acetate, dried over sodium sulfate, and purified by silica-gel chromatography (0-30% hexanes/ethyl acetate) to afford the title compound as a colorless oil (2.91 g, 58%): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.24 (m, 2 H) 7.12-7.18 (m, 2 H) 4.11 (q, J=7.22 Hz, 2 H) 3.55-3.60 (m, 3 H) 2.55-2.59 (m, 3 H) 2.39 (s, 3 H) 1.03 (t, J=7.12 Hz, 3 H); LCMS (m/z) ES+=332 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+]>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[C:2]1=[O:1])[CH3:18]
Reactant: Oc1ncccc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cn1cccc(C(F)(F)F)c1=O
Yield: 84 %

Procedure:
As described in example 322a, reaction of 2-hydroxy-3-(trifluoromethyl)-pyridine with ethyl bromoacetate and potassium carbonate gave 2 products. The title compound was eluted second and was obtained as a colorless liquid (yield: 84%). MS: m/e=250.1[M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([F:25])([F:24])[C:4]([F:23])([F:22])[C:5]([C:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[N:13]([C:14]=1[CH3:15])[CH2:12][CH2:11][CH2:10]2)=O.[BH3-]C#N.[Na+]>ClC(Cl)C.[Zn+2].[I-].[I-]>[F:27][C:2]([F:1])([F:26])[C:3]([F:24])([F:25])[C:4]([F:23])([F:22])[CH2:5][C:7]1[C:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:9]2[N:13]([C:14]=1[CH3:15])[CH2:12][CH2:11][CH2:10]2
Reactant: Cc1c(C(=O)C(F)(F)C(F)(F)C(F)(F)F)c(-c2ccccc2)c2n1CCC2
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1c(CC(F)(F)C(F)(F)C(F)(F)F)c(-c2ccccc2)c2n1CCC2
Reaction time: 48 h

Procedure:
The solution of 1,1,1,2,2,3,3-heptafluoro-4-(3-methyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)-butan-4-one (0.62 g, 1.6 mmol) in dichloroethane (20 ml) is treated successively with NaCNBH3 (0.42 g, 6.4 mmol) and ZnI2 (0.71 g, 2.24 mmol) and refluxed for 4 days (d). After 2 days, NaCNBH3 (0.42 g, 6.4 mmol) and ZnI2 (0.71 g, 2.24 mmol) are again added. The reaction is observed by means of GC-MS. After 2 days, 40% of the compound employed is reacted, and after 4 days 89%, in addition to a further 11% of starting material. The reaction is then terminated by addition of dilute phoshoric acid (8%, 50 ml). After the evolution of gas has ended, the mixture is extracted with methylene chloride, the organic phase is washed with water (50 ml) and the solvent is stripped off in vacuo after drying over Na2SO4 sicc. The residue (0.65 g, 82.4%, 77% strength according to GC-MS(TIC)) is employed in the subsequent reaction without further purification.
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][C@H:8]([CH2:19]O)[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.Cl.C([O-])([O-])=O.[K+].[K+].[N:29]#CBr>C(O)C>[C:13]1([S:10]([CH2:9][C@H:8]2[CH2:19][O:21][C:6]([NH2:29])=[N:7]2)(=[O:11])=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CS(=O)(=O)c1ccccc1
Reactant: N#CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC1=N[C@@H](CS(=O)(=O)c2ccccc2)CO1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
((R)-2-Benzenesulfonyl-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester (0.29 g, 0.92 mmol) was dissolved in ethanol (2 ml), hydrochloric acid in ethanol (5M, 5 ml) was added and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated and the residue was taken up in tetrahydrofuran (5 ml). K2CO3 (0.326 g, 2.36 mmol) and cyanogen bromide (0.136 g, 1.29 mmol) were added. The mixture was stirred overnight and afterwards partitioned between ethyl acetate and water. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=95:5 to yield a white solid, (0.062 g, 28%); MS (ISP): 241.1 ((M+H)+.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[C:35]([CH3:36])=[N:34][CH:33]=[N:32]3)=[C:27]([F:37])[CH:26]=2)[N:20]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[I-].[Na+]>CC(C)=O>[F:37][C:27]1[CH:26]=[C:25]([NH:24][C:21]2[N:20]=[C:19]3[CH:6]([C:7]4[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=4)[CH2:5][CH2:4][CH2:3][CH2:2][N:23]3[N:22]=2)[CH:30]=[CH:29][C:28]=1[N:31]1[C:35]([CH3:36])=[N:34][CH:33]=[N:32]1
Reactant: Cc1ncnn1-c1ccc(Nc2n[nH]c(C(CCCCCl)c3ccc(OCC(F)(F)F)cc3)n2)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ncnn1-c1ccc(Nc2nc3n(n2)CCCCC3c2ccc(OCC(F)(F)F)cc2)cc1F
Yield: 39.2 %

Procedure:
A solution of 5-(5-chloro-1-(4-(2,2,2-trifluoroethoxy)phenyl)pentyl)-N-(3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (2.11 g, 3.92 mmol), sodium iodide (2.94 g, 19.6 mmol), and diisoproplylethylamine (0.685 mL, 3.92 mmol) in acetone (30 mL) was heated in a sealed vessel at 100° C. for 12 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 770 mg (38% yield) of the titled compound as an off-white solid. This material was recrystallized from EtOH (20 mL) to afford 424 mg (22% yield) of the titled compound as a crystalline white solid. LC-MS (M+H)+ 502.5. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.96 (s, 1 H), 7.67 (dd, J=12.8, 2.4 Hz, 1H), 7.24 (t, J=8.5 Hz, 1 H), 7.13 (d, J=8.9 Hz, 2 H), 7.02 (dd, J=9.2, 2.1 Hz, 1 H), 7.00 (s, 1 H), 6.93-6.98 (m, 2H), 4.36 (q, J=8.2 Hz, 2 H), 4.29 (dd, J=8.5, 2.1 Hz, 1 H), 4.22-4.27 (m, 2 H), 2.40 (s, 3 H), 2.17-2.30 (m, 1 H), 2.04-2.13 (m, 1 H), 1.82-2.02 (m, 4 H).
Reaction SMILES: C([O:4][C@H:5]([C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[C:18](OC(CC(N1CCOCC1)=O)C(O)=O)(=O)C.O1CCOCC1.C([O-])(O)=O.[Na+]>CO>[CH3:18][O:9][C:7](=[O:8])[CH2:6][C@H:5]([OH:4])[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11]
Reactant: CC(=O)O[C@@H](CC(=O)O)C(=O)N1CCOCC1
Reactant: CC(=O)OC(CC(=O)N1CCOCC1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of (S)-3-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid and 2-Acetoxy-4-morpholin-4-yl-4-oxo-butyric acid (11 g, 44.8 mmol) in dry methanol (30 mL) HCl in dioxane (4M, 7.3 ml, 29.16 mmol) was added and stirred at room temperature for 5 hrs. The reaction mixture was neutralized with solid NaHCO3, filtered through a mixture of Celite/Na2SO4 (1:1) and concentrated under reduced pressure. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: OC1CCNCC1
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCC(O)CC3)c1C)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol), piperidin-4-ol (1.2 eq.), HOBt (1.21 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (0.2 M) was stirred at rt for overnight. The reaction was concentrated, diluted with DCM, washed with water, dried and concentrated. The residue was triturated with ethyl ether to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH2:21]([NH2:30])/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: NC/C=C/c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc2c(NC/C=C/c3ccccc3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of a solution of 438 mg (2.0 mmol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 339 mg (2.0 mmol) of trans-cinnamylamine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 341 mg (yield: 54.0%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH3:4].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH:3]([C:6]1[N:7]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=[CH:10][CH:9]=2)([CH3:4])[CH3:5]
Reactant: CCOC(=O)Cc1c(C(C)C)[nH]c2cccc([N+](=O)[O-])c12
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(C)C)n(CC(=O)OCC)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (45 mg of a 60% dispersion in mineral oil, 1.13 mmol) was added to a solution of ethyl (2-isopropyl-4-nitro-1H-indol-3-yl)acetate from Step E (300 mg, 1.03 mmol) in DMF (10 mL). After 5 min, ethyl bromoacetate (0.126 mL, 1.13 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CHCl3 (3×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=377 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6].[H][H]>N.CO.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: [H][H]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Yield: 87.1 %

Procedure:
A solution of 3,5-difluorobenzonitrile (0.0345 mol) in ammonia saturated methanol (100 ml) and methanol washed Raney nickel were shaken together under 50 psi of hydrogen for 11/2 hours. The reaction mixture was filtered, the filtrate concentrated then dissolved in ethyl acetate. The product was extracted into 3N aqueous hydrogen chloride. The acidic solution was cooled and basified with 50% sodium hydroxide then was extracted into ethyl acetate. The organic extract was dried over sodium sulfate, filtered and concentrated to yield 4.3 g (86%) yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[C:16]([CH2:24][C:25](O)=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:16]([CH2:24][C:25]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[C:12]([O:14][CH3:15])=[O:13])=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Reactant: O=C(O)CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(NC(=O)CC(=O)c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of 2.1 grams of dimethyl 3-aminophthalate, 1.4 grams of benzoylacetic acid and 2.9 grams of dicyclohexlcarbodiimide is dissolved in 15 ml of tetrahydrofuran and the mixture is stirred at room temperature for eighteen hours. The insoluble matter are removed by filtration, the filtrate is concentrated, and 1.9 grams of dimethyl 3-benzoylacetylaminophthalate, colorless crystals, melting point 100° to 103° C. is obtained. This (1.9 grams) is dissolved in 30 ml of methanol, heated to reflux for four hours with 0.48 grams of sodium hydride, cooled, adjusted to pH 3 with diluted hydrochloric acid, crystals separated out therefrom are collected by filtration and recrystallized from methanol to give 1.3 grams of methyl 3-benzoyl-4-hydroxy-2-quinolone-5-carboxylate, pale yellow needles, melting point 263° to 265° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]1=[O:1]
Reactant: BrBr
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CCCC(Br)C1=O
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-oxocyclohexanecarboxylate (50 g, 0.29 mol) in CHCl3 (150 mL) there was slowly added bromine (47 g, 0.29 mol) at 0° C. under a blanket of nitrogen as inert gas dropwise over a period of 45 minutes and the resultant mixture was stirred for a period of 6 hours at 0° C. and then for 16 hours at room temperature. Air was then passed into the reaction solution over a period of 2 hours. The organic phase was washed with aqueous saturated NaHCO3 solution (2×15 mL) and aqueous saturated NaCl solution (3×20 mL). Following drying of the organic phase over Na2SO4 and filtration, the solvent was removed. The product ethyl 3-bromo-2-oxocyclohexanecarboxylate was obtained in a yield of 72.6 g (corresponding to 99% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1F
Reactant: COC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1F
Reaction time: 0.05 h
Yield: 115.4 %

Procedure:
40% Methanolic Triton B (0.14 mL, 0.31 mM) was added to a solution of the 9-[(2-fluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (51.9 mg, 0.155 mM) in 5 mL DMF at room temperature. After 3 minutes, methyl bromoacetate (110.5 mg, 0.72 mM) was added and the resultant mixture stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 72.8 mg (71%) of the {9-[(2-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (DMSO-d6) δ7.65 (d, 1H, J=8 Hz), 7.5 (s, 1H), 7.4-7.2 (m, 5H), 7.15 (s, 1H), 7.1 (d, 1H, J=8 Hz), 7.05 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.85 (s, 2H), and 3.7 (s, 3H). IR (CHCl3, cm−1) 3436, 1763, 1675, 1457, 1327, 1208, 1198, 1150, 1102, 772, 756, and 719. MS (FD) m/e 407.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)C(C)C)(C)C.[C:16]([C:20]1[N:24]([CH2:25][CH:26]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]2)[C:23]2[CH:34]=[CH:35][C:36]([S:38](Cl)(=[O:40])=[O:39])=[CH:37][C:22]=2[N:21]=1)([CH3:19])([CH3:18])[CH3:17]>ClCCl.CCOC(C)=O>[C:16]([C:20]1[N:24]([CH2:25][CH:26]2[CH2:27][CH2:28][C:29]([F:33])([F:32])[CH2:30][CH2:31]2)[C:23]2[CH:34]=[CH:35][C:36]([S:38]([N:5]3[CH2:6][CH:3]([OH:2])[CH2:4]3)(=[O:39])=[O:40])=[CH:37][C:22]=2[N:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: OC1CNC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(O)C3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 0 °C
Yield: 77 %

Procedure:
3-Hydroxyazetidine hydrochloride (162 mg, 1.5 mmol) was dissolved in 7 mL of dry dichloromethane. N,N-diisopropylethylamine (0.7 mL, 4 mmol) was added and the mixture was cooled down to 0° C. 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (400 mg, 1 mmol) was slowly added to the reaction mixture which was allowed to warm to room temperature for 2 hours. The mixture was diluted with EtOAc which washed with water then brine and dried over Na2SO4. The solvent was removed in vacuo to give a crude product that was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 340 mg (62%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.56-1.66 (m, 2 H), 1.69 (s, 9 H), 1.73-1.84 (m, 4 H), 2.01-2.14 (m, 3 H), 3.45-3.51 (m, 2 H), 4.01 (dd, J=8.79, 6.84 Hz, 2 H), 4.34-4.43 (m, 1 H), 4.58 (d, J=7.62 Hz, 2 H), 7.97 (dd, J=8.79, 1.56 Hz, 1 H), 8.13 (d, J=8.79 Hz, 1 H), 8.18 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=442.3; Anal. Calc. for C21H29F2N3O3S+4.9C2HO2F3+5.0H2O+2.7 CH3CN: C, 39.47; H, 4.14; N, 6.31. Found: C, 39.48; H, 4.14; N, 6.30
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[O:17][C:7]1=[N:8][C:9]([F:16])=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=[C:6]1[C:5]2=O.[CH3:22][Mg]Br.Cl.CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[O:17][C:7]1=[N:8][C:9]([F:16])=[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=[C:6]1[C:5]2=[CH2:22]
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)c1cc2c(=O)c3cc(Br)ccc3oc2nc1F
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1c2cc(Br)ccc2Oc2nc(F)c([Si](C)(C)C)cc21

Procedure:
7-bromo-2-fluoro-3-(trimethylsilyl)-5H-chromeno[2,3-b]pyridin-5-one (1.05 g, 2.9 mmol) was dissolved in dry THF (30 mL) and treated with methylmagnesium bromide (3.0 M in diethyl ether, 2.0 mL, 6.00 mmol). After 15 minutes 5N HCl (30 mL) was added followed by EtOAc (100 mL) and water (100 mL). The phases were mixed and separated and the organics were dried with magnesium sulfate before evaporating to dryness under reduced pressure. Purification using silica chromatography (hexane to dichloromethane gradient) gave the desired 7-bromo-2-fluoro-5-methylene-3-(trimethylsilyl)-5H-chromeno[2,3-b]pyridine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:45][C:44]5[CH:43]=[CH:42][C:41]([N:38]6[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]6)=[CH:47][CH:46]=5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 4-(4-methylpiperazin-1-yl)aniline with yield 82 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (br. s., 4 H) 1.73 (br. s., 2 H) 1.99 (br. s., 2 H) 2.22 (s, 3 H) 2.45 (br. s., 4 H) 3.09 (br. s., 4 H) 3.94 (s, 3 H) 4.08 (t, J=13.89 Hz, 2 H) 4.84 (br. s., 1 H) 6.91 (d, J=8.84 Hz, 2 H) 7.26 (d, J=6.32 Hz, 1 H) 7.56 (d, J=8.59 Hz, 2 H) 8.08 (s, 1 H) 8.18-8.41 (m, 2 H) 9.91 (br. s., 1 H). [M+H] calc'd for C32H37F3N8O3, 639; found 639.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:22]C(=O)C)([CH2:20][OH:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:8][CH:7]=1.[ClH:26]>>[CH3:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([NH2:22])([CH2:2][OH:1])[CH2:20][OH:21])=[CH:7][CH:8]=1.[ClH:26]
Reactant: CCCCCCCCc1ccc(CCC(CO)(CO)NC(C)=O)cc1
Agent: Cl
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
N-(1-Hydroxy-2-(hydroxymethyl)-4-(4-octylphenyl)butan-2-yl) acetamide (23.5 g) is charged into a 250 mL single-neck round bottom flask equipped with a condenser and 3N hydrochloric acid (100 mL) is added. The mixture is heated to 100° C. and stirred for 3 hours. The mass is cooled to room temperature and maintained overnight. The mass is extracted with ethyl acetate (3×100 mL) and the ethyl acetate extracts are combined, dried with sodium sulphate, and concentrated under vacuum to produce a gummy solid. Ethanolic hydrochloride solution is added to the solid, stirred for 3 hours at room temperature and the obtained solid is separated by filtration and suction dried. The solid is recrystallized from an isopropyl alcohol solution to give fingolimod hydrochloride. Yield: 5.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=O)=[CH:8]2.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:13]=[CH:16][C:17]([OH:19])=[O:18])=[CH:8]2
Reactant: O=C(O)CC(=O)O
Reactant: COc1cccc2cc(C=O)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cccc2cc(C=CC(=O)O)ccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Methoxynaphthalene-2-aldehyde (0.1 mole), malonic acid (0.2 moles), and dry pyridine (175 ml) are placed in a 1 1 round-bottom flask. The malonic acid is dissolved by shaking on a steam bath and piperidine (0.5 ml) is added. The reaction is allowed to take place on the steam bath for 4 hours. After standing at room temperature overnight, the mixture is refluxed for 1 hour and cooled. The reaction mixture is poured into 250 ml of ice water and acidified with concentrated hydrochloric acid (80 ml) with stirring. The product is collected by filtration, washed with water (4 × 150 ml) and air dried to give β-(5-methoxynaphth-2-yl)propenoic acid.