Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].CCN(C(C)C)C(C)C>CC(O)C>[C:12]([N:19]1[CH2:20][CH2:21][N:22]([C:6]2[N:7]=[CH:2][C:3]3[CH2:10][C:9](=[O:11])[NH:8][C:4]=3[N:5]=2)[CH2:23][CH2:24]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc3c(n2)NC(=O)C3)CC1
Reaction time: 14 h

Procedure:
A solution of 4-chloro-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (prepared according to the literature: Li Sun et al. Bioorg. and Med. Chem. Lett. 2002, 12, 2153-2157; 690 mg, 3.7 mmol), Boc-piperazine (630 mg, 3.7 mmol), and DIEA (0.96 mL, 5.5 mmol) in 20 mL IPA was heated to reflux and stirred 14 hours, after which the reaction mixture was concentrated. The crude was purified on silica gel (1:2 DCM:EtOAc to 1:4 DCM:EtOAc gradient) to give 4-Boc-piperazin-1-yl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one, which was used in the next step.
Reaction SMILES: C1(S([CH:10]2[CH:15](S(C3C=CC=CC=3)(=O)=O)[CH:14]3[CH2:25][CH2:26][CH:11]2[CH:12]=[CH:13]3)(=O)=O)C=CC=CC=1.[N+:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])#[C-:28].CC(C)([O-])C.[K+].Cl>O1CCCC1>[CH2:33]([O:32][C:30]([C:29]1[NH:27][CH:28]=[C:15]2[C:10]=1[CH:11]1[CH2:26][CH2:25][CH:14]2[CH:13]=[CH:12]1)=[O:31])[CH3:34]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=S(=O)(c1ccccc1)C1C2C=CC(CC2)C1S(=O)(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc2c1C1C=CC2CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A reaction system of a mixed solution of 7.76 g (20 mmol) of the resultant 5,6-bis(phenylsulfonyl)-bicyclo[2,2,2]octa-2-ene and 50 ml of anhydrous tetrahydrofuran was replaced with nitrogen. Then, 2.425 ml (22 mmol) of ethyl isocyanoacetate were added to the mixed solution, and the whole was cooled to 0° C. Potassium tert-butoxide (50 ml/l M THF solution) was dropped into the mixture in 2 hours, and the whole was stirred at room temperature for 3 hours. After the completion of the reaction, diluted hydrochloric acid was added to the reaction mixture. Then, the reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, distilled water, and a saturated salt solution in this order, and was dried with anhydrous sodium sulfate. The dried product was purified by means of silica gel column chromatography (chloroform) to yield ethyl-4,7-dihydro-4,7-ethano-2H-isoindole-1-carboxylate (3.5 g, 16 mmol, 80% yield).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH3:2].[NH2:9][C:10]1[C:11]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:12][C:13]([CH3:31])=[C:14]([CH3:30])[C:15]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].Cl.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:16]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:15]2[C:14]([CH3:30])=[C:13]([CH3:31])[N:12]=[C:11]([O:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:10]=2[N:9]=1
Reactant: COC(C)(OC)OC
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCNC(=O)OC(C)(C)C)c1C
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCCNC(=O)OC(C)(C)C)c2c1C
Yield: 83.1 %

Procedure:
Trimethyl orthoacetate (3.55 mL, 28.27 mmol), tert-butyl 2-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]ethoxy}ethylcarbamate (11.21 g, 26.92 mmol), pyridine hydrochloride (1.12 g) and toluene (120 mL) were combined and heated at reflux for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL), washed with water (3×100 mL) and brine (1×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure to provide 9.85 g of tert-butyl 2-[2-(2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethylcarbamate.
Reaction SMILES: [CH2:1]([C:8]1[C:9](Cl)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[CH3:45][N:46]1[CH:50]=[CH:49][N:48]=[C:47]1[Sn](CCCC)(CCCC)CCCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:8]1[C:9]([C:47]2[N:46]([CH3:45])[CH:50]=[CH:49][N:48]=2)=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[CH:15][C:14]([C:19]([C:31]1[N:35]([CH3:36])[CH:34]=[N:33][CH:32]=1)([C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[OH:20])=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccccc3)c(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(-c3nccn3C)c(Cc3ccccc3)c(Cl)c2c1
Temperature: 110 °C

Procedure:
A mixture of (3-benzyl-2,4-dichloroquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (1.01 g, 1.86 mmol, Example 109), 1-methyl-2-(tributylstannyl)-1H-imidazole (1.42 g, 3.68 mmol), Pd(PPh3)4 (206 mg, 0.180 mmol), and toluene (10 mL) was sparged with N2 for about 10 minutes, then heated at 83° C. for 16 hours and 110° C. for 3 hours. After cooling down to room temperature, the mixture was concentrated in vacuo and DCM was added. The precipitated solid was filtered and dissolved in DMSO and MeOH. A few drops of TFA were added to improve solubility. The mixture was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, MeOH-d4) δ 9.06 (s, 1H), 8.94 (s, 1H), 8.86 (d, J=2.02 Hz, 1H), 8.54 (d, J=2.02 Hz, 1H), 8.22 (d, J=9.09 Hz, 1H), 8.16 (dd, J=2.02, 8.08 Hz, 1H), 7.90-7.94 (m, 2H), 7.64 (d, J=1.52 Hz, 1H), 7.19-7.26 (m, 3H), 7.18 (d, J=1.52 Hz, 1H), 6.86-6.90 (m, 2H), 4.54 (s, 2H), 3.74 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:40])([CH3:39])[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:38]=[CH:37][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:12]=[N:11]1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O.C(=O)=O>>[CH3:40][C:8]([NH2:7])([CH3:39])[CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:38]=[CH:37][C:18]3[C:19]4[N:20]=[C:21]([C:27]5[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=5)[S:22][C:23]=4[CH2:24][CH2:25][O:26][C:17]=3[CH:16]=2)[CH:12]=[N:11]1
Reactant: CC(C)(Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1)NC(=O)OC(C)(C)C
Agent: O=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(N)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Yield: 15 %

Procedure:
To a round bottom flask containing [1,1-Dimethyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-ethyl]-carbamic acid tert-butyl ester (0.175 g, 0.000297 mol) in methylene chloride (1.1 mL, 0.017 mol) was added trifluoroacetic acid (1.3 mL, 0.017 mol). The solution was stirred at room temperature until CO2 evolution stopped (30 minutes). The solvent was removed in vacuo and purified by reverse-phase HPLC to give 393 (21.8 mg) as a white solid. MS(ESI+) 490.1. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=9.7, 1H), 8.29 (s, 1H), 8.26 (d, J=8.3, 1H), 7.98 (s, 1H), 7.49 (dd, J=8.3, 1.7, 1H), 7.37 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.39 (t, J=5.0, 2H), 3.47 (t, J=5.0, 2H), 2.86 (s, 2H), 1.50 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[Br:23][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: CC(Br)c1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Yield: 85.4 %

Procedure:
19 g of 4'-ethyl-4-benzoyl-biphenyl, 12.4 g of N-bromosuccinimide and 0.12 g of azaisobutyronitrile in 400 mL of carbon tetrachloride were heated to boiling under reflux for 1.5 hours. After filtering off the precipitated material the solution was evaporated and the residue was recrystallized from cyclohexane. There were obtained 20.7 g (85%) of 4'-(1-bromo-ethyl)-4-benzoylbiphenyl as a colorless solid with a m.p. of 132°-134° C.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.O.[CH3:25][C:26]1([CH3:38])[O:31][C:30](=[O:32])[C:29]([CH2:33][CH2:34][C:35](=[O:37])[CH3:36])=[CH:28][O:27]1>C(OCC)(=O)C>[CH3:38][C:26]1([CH3:25])[O:31][C:30](=[O:32])[C:29]([CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])=[CH:28][O:27]1
Reactant: CC(=O)CCC1=COC(C)(C)OC1=O
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)CCC1=COC(C)(C)OC1=O
Temperature: 32 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
30 g of baker's yeast (made by Oriental Yeast Co., Ltd.) and 15 g of saccharose were added in 30 ml of tap water, and the solution was then stirred at 32° C. for 30 minutes. Afterward, 350 mg of 2,2-dimethyl-5-(3-oxobutyl)-1,3-dioxin-4-one were added thereto, and the solution was then stirred overnight at the same temperature. 7.5 g of saccharose were further added thereto, followed by stirring overnight. Water of the reaction solution was then distilled off under reduced pressure, and the resultant residue was extracted with dichloromethane and then dried over anhydrous sodium sulfate. Afterward, the solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=4:1), thereby obtaining 161 mg (yield 55%) of (-)-2,2-dimethyl-5-(3-hydroxybutyl)-1,3-dioxin-4-one [a compound having the formula (1) in which n is 2, X is a hydrogen atom, Y is a hydrogen atom, and a substituent is present at the 5-position].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH:45](I)I>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: IC(I)COCCOCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCOCCOCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4 hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 120 mg of powdered potassium carbonate and 0.4 ml of 1,2-bis(diiodoethoxy)ethane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethylacetate 4:1). The product is obtained as an oil. C30H32F2INO5 (651) MS (ESI): M+-18
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]2)[CH:3]=1.[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]>CCOC(C)=O>[C:14]([O:18][C:19](=[O:27])[NH:20][C:21]1[S:22][C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3([C:12]#[N:13])[CH2:11][CH2:10][CH2:9]3)[CH:3]=2)=[C:24]([CH3:26])[N:25]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)n1
Reactant: N#CC1(c2cc(Br)ccn2)CCC1
Solvent: CCOC(C)=O
Product: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
The title compound is prepared in analogy to the procedure described in Step 40.3, but using 1-(4-bromo-pyridin-2-yl)-cyclobutanecarbonitrile (Step 50.3) and (4-methyl-thiazol-2-yl)-carbamic acid tert-butyl ester (Step 17.4). The reaction mixture is stirred for 3 h at 100° C. Title compound: ESI-MS: 371.1 [M+H]+; tR=4.86 min (System 1); TLC: Rf=0.66 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[Cl:27]Cl.O>C(O)(=O)C>[Cl:27][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[S:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Reactant: ClCl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2nc3ccccc3sc-2c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 500 g (2.34 mol) of 3H-phenothiazin-3-one in 12.5 liters of glacial acetic acid was added 1.25 kg of potassium dichromate. The mixture was stirred at room temperature for 1/2 hour. To this resulting mixture was then added 2.34 mol of a 1M solution of chlorine in glacial acetic acid dropwise over a period of 4 hours. The progress of the reaction was monitored by tlc to ensure no excess chlorine was added. After addition of chlorine was completed the mixture was stirred at room temperature for another 1/2 hour and was then poured into 120 liters of H2O with vigorous stirring. The 4-chloro-3H-phenothiazin-3-one precipitated was allowed to settle overnight. The majority of the aqueous solution was siphoned and discarded and the rest was filtered. The filtered precipitate was washed thoroughly with water and then rinsed with methanol and was allowed to dry to give 504 g crude 4-chloro-3H-phenothiazin-3-one which was recrystallized from toluene, m.p. 221°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:2]=1.[H-].[Na+].[CH3:17]I.O>CN(C)C=O>[CH3:17][N:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: CI
Reactant: O=C(NCc1cccnc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccnc1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
4.08 g of N-(3-pyridylmethyl)trifluoroacetic acid amide was dissolved in 40 ml dimethylformamide, and then stirred with 880 mg of 60% sodium hydride on ice for 15 minutes. 1.47 ml methyl iodide was added to the reaction mixture on ice, followed by stirring at room temperature for 4 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (chloroform:methanol=50:1) to provide N-methyl-N-(3-pyridylmethyl)trifluoroacetic acid amide (3.71 g, 85%) as a pale yellow oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].[CH2:24]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:24]([N:28]([CH2:29][CH2:30][CH2:31][OH:32])[C:2]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[S:3])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCCCO
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Solvent: ClCCl
Product: CCCCN(CCCO)C(=S)Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A mixture of 10 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine, 6.3 parts of 3-(butylamino)-1-propanol and 130 parts of dichloromethane was stirred for 3 hours at room temperature. The reaction mixture was evaporated and the residue was triturated in 2-propanone. The product was filtered off and dried, yielding 12.7 parts (92%) of N-butyl-N-(3-hydroxypropyl)-N'-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 153.9° C. (44).
Reaction SMILES: C(O[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][NH2:8])C.[OH-].[Na+].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16]>C(Cl)Cl>[C:14]([N:8]1[CH:4]([O:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]1)(=[O:17])[CH:15]=[CH2:16]
Reactant: CCOC(CCCN)OCC
Reactant: C=CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CC(=O)N1CCCC1OCC
Temperature: 15 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
4-Aminobutyraldehyde diethyl acetal (AmBDA, 75 g, 1.09 mol, Aldrich Chemical) was combined with a two phase mixture of 955 mL of CH2Cl2 and 160 mL of 14 N NaOH in a 3 neck flask equipped with a thermometer and an efficient mechanical stirrer. This was cooled to 15° C. with an ice bath. Acryloyl chloride (98.3 g, 1.09 mol. Aldrich) was added via an addition funnel at a rate slow enough to maintain the reaction temperature below 30° C. Reaction monitoring by capillary glpc revealed essentially complete AmBDA consumption when the acryloyl chloride addition was complete. Agitation was continued for 1 h. The layers were separated (water may be added to dissolve precipitated salt and improve phase separation) and the organic phase was washed with saturated brine. The brine was combined with the aqueous layer and back extracted with CH2Cl2 . The combined organic layers were neutralized with saturated aqueous NaH2PO4, dried over anhydrous MgCl2 and concentrated on a rotary evaporator at 40° C. to give 99% pure ABDA (by glpc) in 87% yield. The product can be freed of any high molecular weight by-products by kugelrohr distillation (120°-125° C. at 0.2 torr), but this produces significant yield losses and partial isomerization to N-acryloyl-5-ethoxy pyrrolidine (AEP) and related products. The pot temperature should not exceed 60° C. during these operations. The yield loses are minimized by adding a basic reagent, such as Na2CO3 , and a radical inhibitor, such as methylene blue, to the distillation vessel.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1C(=O)N(Br)C(=O)C1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:11][C:9]1[C:10]2=[C:2]([CH2:1][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: OC1CCNCC1
Reactant: CSc1ncnn2ccc(C)c12
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (200 mg, 1.12 mmol), NBS (218 mg, 1.23 mmol), and AKIN (spatula tip) in carbon tetrachloride (4 mL) was heated at 80° C. for 1 h. After cooling to rt, the solution was filtered to remove succinimide. To the filtrate was added 4-hydroxypiperidine (126 mg, 1.34 mmol, Aldrich) and DIPEA (214 μL, 1.23 mmol). The reaction was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (229 mg, 74%) as a colorless solid. 1 H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.88 (d, 1H, J=2 Hz), 6.81 (d, 1H, J=2 Hz), 4.54 (br s, 1H), 3.76 (s, 2H), 3.48-3.44 (m, 1H), 2.75-2.71 (m, 2H), 2.62 (s, 3H), 2.10-2.08 (m, 2H), 1.70-1.68 (m, 2H), 1.38-1.36 (m, 2H); MS(ESI+) m/z 279.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7](=[NH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)C.Cl.[CH2:21]([O:23][C:24](=[O:32])[CH:25](N)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:22]>N1C=CC=CC=1>[CH2:21]([O:23][C:24](=[O:32])[CH:25]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:16])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:22]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: N=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC

Procedure:
A suspension of 9.2 g. of 5-chloro-2-hydroxy-benzophenone imine in 60 ml. of ethanol is treated with 12.6 g. of aminomalonic acid diethyl ester hydrochloride and 5.0 ml. of pyridine and the mixture boiled at reflux for 1 hour while stirring. The mixture is then concentrated to dryness under reduced pressure and the residue partitioned between toluene and water. The organic phase is washed with water, briefly dried over sodium sulfate and evaporated to dryness. The residual oily residue crystallizes upon trituration with hexane. There is obtained [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester, having a melting point of 55°-56° C. Recrystallization from ethanol yields gold-yellowish leaflets having the same melting point.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S+:14]([O-])[CH2:15][C:16](N)=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.C1(C(C2C=CC=CC=2)[OH:27])C=CC=CC=1.NC(N)=S.Br.ClCC(O)=O>>[C:4]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[S:14][CH2:15][C:16]([OH:17])=[O:27])[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Br
Agent: NC(N)=S
Agent: O=C(O)CCl
Product: O=C(O)CSC(c1ccccc1)c1ccccc1

Procedure:
Scheme 2 describes an industrial method for the preparation of Modafinil (II) wherein the all the reaction steps may be carried out in situ. In this scheme, the starting material is diphenylmethanol which is reacted with thiourea in the presence of HBr followed by basic hydrolysis and reaction with chloroacetic acid to form compound III. Hydrogen peroxide is then passed through the reaction mixture followed by acidification with hydrochloric acid to form (benzhydrylsulfinyl)acetic acid. The acid is reacted with dimethyl sulphate in presence of soda lye and sodium bicarbonate to obtain methyl(benzhydrylsulfinyl)acetate. After filtration methyl(benzhydrylsulfinyl)acetate is dissolved in methanol and ammonia is bubbled through the reaction mixture. After recrystallization and drying of the reaction mass Modafinil (II) is obtained with 41% total yield calculated from benzhydrol. The in-situ reaction scheme 2 is set out below.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9].C(O)C.[CH2:14]([NH:21][C@@H:22]([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH2:14]([NH:21][CH:22]([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]2[CH:3]1[C@H:4]2[C:8]([OH:10])=[O:9]
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: O=C1CCC2C1[C@H]2C(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
To a solution of crude (±)(6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid (11.9 g, 84.9 mmol, assume 100% potency) in 119 mL of 6:1 ethyl acetate:ethanol at reflux is added 18 g (85.1 mmol) of (S)—N-benzyl-α-methylbenzyl-amine. Upon dissolution, the mixture is allowed to cool optionally followed by seeding at 52° C. Upon cooling to room temperature and stirring an additional 13.5 h, the crystals are collected and washed with 6:1 ethyl acetate:ethanol (2×48 mL). Drying in vacuo gave 10.8 g (36%, 77% de) of the resolved salt as a solid.