Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH:15]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>O1CCCC1>[CH:15]1([CH2:21][C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 20.6 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), cyclohexylacetyl chloride (0.80 g, 6.0 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (24 mL) provided 2-cyclohexyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-acetamide (0.32 g). Mp 189-191° C.; MS m/z 312 ([M+H]+); Anal. Calcd. for C20H25NO2: C, 77.14; H, 8.09; N, 4.50; Found: C, 77.44; H, 8.08; N, 4.59.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12](=[CH2:15])[CH2:13][OH:14].[OH-].[K+].O>CS(C)=O>[CH3:15][C:12]([CH2:13][O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])=[CH2:11]
Reactant: C=C(C)CO
Reactant: N#Cc1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(C)COc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
A solution of 30.0 grams (0.174 mole) of 2,6-dichlorobenzonitrile and 14.7 mL (0.174 mole) of 2-methyl-2-propen-1-ol in 200 mL of dimethyl sulfoxide is stirred, and 12.7 grams (0.191 mole) of 85% potassium hydroxide is added portionwise during a 5 minute period. During the addition, the reaction mixture temperature rises from 20° C. to about 35° C. Upon completion of the addition, the reaction mixture is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is poured into 600 mL of water. The mixture is filtered to collect a solid. The solid is washed with water and dried under vacuum, yielding 33.9 grams of 2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]3[CH:16]=[CH:17][CH:18]=[C:7]23)[CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[ClH:33]>O1CCOCC1>[ClH:33].[NH:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]3[CH:16]=[CH:17][CH:18]=[C:7]23)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Yield: 76 %

Procedure:
A 5 L 3-neck round bottom flask was fitted with a mechanical stirrer, an addition funnel, a temperature probe/controller and a nitrogen inlet/outlet. The vessel was charged under nitrogen with a clear amber solution of tert-butyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate and (50 g, 0.15 mol) and toluene (250 mL). Stirring was commenced and the addition funnel was charged with (73 mL, 0.29 mol) of 4M HCl in 1,4-dioxane which was added dropwise over 10 minutes resulting in a very dark solution. The mixture was continued to stir at ambient temperature for 1 h before the reaction mixture was filtered to remove the residual solids. The filtrate was concentrated under reduced pressure to provide a solid which was triturated with diethyl ether (2×200 mL) and was then dried under vacuum to provide (31 g, 76%) of spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]hydrochloride as an off-white solid. ESI-MS m/z calc. 240.1. found 241.3 (M+1)+. Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 9.45 (s, 2H), 7.76-7.62 (m, 1H), 7.55 (dd, J=2.8, 1.3 Hz, 1H), 7.23-7.08 (m, 3H), 6.31 (t, J=3.2 Hz, 1H), 6.11 (dd, J=3.4, 1.3 Hz, 1H), 3.29-3.13 (m, 4H), 2.25 (td, J=14.4, 5.0 Hz, 2H), 2.09 (d, J=14.1 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=1)[CH3:2].[C:23]([NH:26][NH2:27])([NH2:25])=[NH:24].[ClH:28].Cl.O>C(O)C>[ClH:28].[CH2:1]([C:3]1[C:11]2[C:10](=[N:27][NH:26][C:23]([NH2:25])=[NH:24])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:4]=1)[CH3:2]
Reactant: N=C(N)NN
Reactant: CCc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 284.9 %

Procedure:
A mixture of 3-ethyl-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.25 g), aminoguanidine hydrochloride (0.091 g), concentrated hydrochloric acid (0.039 ml), water (0.039 ml) and ethanol (30 ml) was refluxed for 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethyl acetate and water to give 3-ethyl-4-guanidinoimino-1-methanesulfonyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 14) (0.92 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>ClCCl>[C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[NH:20][CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 2-amino-4-(4-methyl-piperazin-1-yl)-benzoic acid tert-butyl ester (11.5 g, 39.5 mmol) in dichloromethane (340 mL) were added tetrahydro-pyran-4-one (4.5 mL, 49.3 mmol), trifluoroacetic acid (8.2 mL) and tetramethylammonium triacetoxyborohydride (15.57 g, 59.2 mmol). The mixture was stirred at room temperature for 2 hours then washed with 0.5N hydrochloric acid, with 0.5N NaOH and with a saturated solution of NaHCO3. The organic layer was dried over sodium sulfate and evaporated to dryness affording the title compound as a pale yellow solid (13.3 g, 90% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)=O.[C-]#N.[K+].CN(C)[C:18]1([C:23]#[N:24])[CH2:22]CC[CH2:19]1>O>[N:2]1([C:18]([CH3:22])([CH3:19])[C:23]#[N:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCNCC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)N1CCCCCC1
Yield: 80 %

Procedure:
The title compound (6.6 g: 80%) was prepared from homopiperidine hydrochloride (6.7 g; 49 mmol), acetone (3.67 ml; 50 mmol), and potassium cyanide (3.25 g; 50 mmol) in water (25 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ 1.43 (6H, s), 1.50-1.65 (8H, m), 2.66 (4H, m).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2>C(Cl)Cl>[Br:1][CH2:15][C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([Br:3])[CH:5]=2)[CH:10]=1)=[O:16]
Reactant: BrBr
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Solvent: ClCCl
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of bromine (0.682 mL, 13.3 mmol) in DCM (20 mL) was added to a solution of 1-(6-bromonaphthalen-2-yl)ethanone (3.30 g, 13.3 mmol) (>90% purity) in DCM (60 mL) and the reaction was stirred at rt overnight. The reaction mixture was concentrated to yield 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g) as an off white solid which was used without further purification. LC-MS retention time 2.177 min; m/z 342.92 (MNa+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 1 H), 8.03-8.10 (m, 2 H), 7.86 (d, J=8.5 Hz, 1 H), 7.85 (d, J=8.8 Hz, 1 H), 7.67 (dd, J=8.8, 2.0 Hz, 1 H), 4.56 (s, 2 H).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:28]3[C@H:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:28]3[C@H:24]([CH2:25][N:26]([C:8](=[O:10])[C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11][CH3:12])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CC[C@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (0.49 g) is added to a solution of (S)-2-phenylbutyric acid (0.5 g) in dry dichloromethane (15 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.98 g) and triethylamine (0.42 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (2×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.6 cm, height 9.7 cm), eluting with a mixture of ethyl acetate and cyclohexane (80/20 by volume) and collecting 30 cc fractions. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). The residue is re-chromatographed on a silica gel column (0.2-0.063 mm, diameter 1.3 cm, height 14.5 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50 cc fractions. Fractions 1 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (3aR,7aR)-7,7-diphenyl-2-[(S)-2-phenylbutyryl]-4-perhydroisoindolone (0.54 g) is obtained in the form of a white meringue. [α]D20 =-216° (c=1, methanol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH2:20][CH3:21])[C:18](=[O:22])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1>>[NH:34]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH2:20][CH3:21])[C:18](=[O:22])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:23]=2)[CH:36]=[N:35]1
Reactant: CCn1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CCn1c(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n[nH]c1=O

Procedure:
Following the procedure of Example 44, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 269. MS: (ESI+) 380.2
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])=[CH2:2].[CH3:13][S:14]([C:17]1[N:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11])[O:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[N:22][CH:21]=1)=[CH2:2]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: C=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 25 h
Yield: 78.8 %

Procedure:
A mixture of 2-ethenyl-4-fluoro-1-nitrobenzene (9.6 g), 6-(methylsulfonyl)pyridin-3-ol (10.0 g), potassium carbonate (8.3 g), and N,N-dimethylformamide (90 mL) was stirred at 60° C. for 25 hr. The reaction solution was concentrated under reduced pressure, to the obtained residue was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (14.5 g, yield 79%) as pale-yellow crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][C@@:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1Nc2cccc3c2[C@@]1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCC[C@@]23CCCc4cccc(c42)NC3=O)CC1
Yield: 83.4 %

Procedure:
(S)-2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (308 mg, 1.0 mmol), 4-(2-methoxyphenyl)piperazine (415 mg, 2.1 mmol) and potassium carbonate (280 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide (10 ml) were stirred at room temperature for 18 hours. Then, ethyl acetate (80 ml) was added to the resulting reaction mixture, which was washed with water and saturated saline solution, successively dried over anhydrous sodium sulfate, followed by evaporating the solvent under reduced pressure. The resulting product was separated and purified by means of silica gel column chromatography, whereby 350 mg (yield 84%) of the above-described object compound could be obtained.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]([NH2:16])=[N:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[C:23]#[C:24][CH2:25][F:26])C>>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C@H:11]2[O:15][C:14]3=[N:16][C:22](=[O:21])[CH:23]=[C:24]([CH2:25][F:26])[N:13]3[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Reactant: CCOC(=O)C#CCF
Product: CC(C)(C)c1ccc(OC[C@@H]2Cn3c(CF)cc(=O)nc3O2)cc1

Procedure:
The title compound was prepared from (S)-5-(4-tert-butyl-phenoxymethyl)-4,5-dihydro-oxazol-2-yl-amine and 4-fluoro-but-2-ynoic acid ethyl ester (prepared in accordance with the procedures as described in Poulter, J Org Chem 1981, 46, 1532) according to the procedures employed for the preparation of the compound in Example 98.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C1CCCCC1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCCC2)C1
Yield: 96.3 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), cyclohexanone (0.11 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 90 mg (96%) of the title compound.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][NH:20][C:21]2(C(N)=O)[CH2:25][NH:24][CH:23]=[N:22]2)=[CH:11][CH:10]=1.CO>ClCCl>[N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][N:20]2[C:21]3[N:22]=[CH:23][NH:24][C:25]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])=[CH:11][CH:10]=1
Reactant: CCOC(=O)N=C=S
Reactant: NC(=O)C1(NCc2ccnc3ccccc23)CNC=N1
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(Cc2ccnc3ccccc23)c2nc[nH]c12
Temperature: 25 °C
Yield: 9 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.5 ml, 4.18 mmol) was added to a solution of 4-[(quinolin-4-ylmethyl)amino]-1H-imidazole-4-carboxamide (0.93 g, crude material from Example 24(a)) dissolved in anhydrous dichloromethane (10 mL) and methanol (5 mL) mixture. After o.n. (over night) at r.t., the solution was concentrated in vacuo and the residue was dissolved in 1N NaOH solution (30 mL) and refluxed for 3.5 h. After cooling to r.t., the pH was adjusted to ˜6.5 with 2 N HCl. The solid that formed was collected by filtration and dried generating 0.35 g of crude material. A portion of the solid (150 mg) was purified by preparative HPLC, and the solid obtained was washed with dichloromethane and ether, generating 25.9 mg (9% yield over two steps) of the title compound.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH:24]([CH3:28])[C:25](Cl)=[O:26])=[CH:21][CH:20]=1.Cl>C(N(CC)CC)C.C(#N)C>[CH2:13]([O:12][C:4](=[O:11])[CH:5]([C:25](=[O:26])[CH:24]([O:23][C:22]1[CH:29]=[CH:30][C:19]([O:18][C:17]2[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:16]=2[Cl:15])=[CH:20][CH:21]=1)[CH3:28])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
Into a 500 ml flask equipped with a stirrer and a dropping funnel 9.52 g of anhydrous magnesium chloride and 100 ml of anhydrous acetonitrile are introduced. To the heterogeneous mixture 16.0 g of diethyl malonate are added, the reaction flask is placed into an ice bath whereupon 28 ml of triethyl amine are added. To the solution at 0° C. 35 g of 2-[4'-(2",4"-dichloro-phenoxy)-phenoxy]-propionyl-chloride are added dropwise within 15 minutes. The reaction mixture is stirred at 0° C. for an hour and at room temperature for 12 hours whereupon it is cooled to 0° C. and 60 ml of a 5M hydrochloric acid solution are added. The solution thus obtained is extracted three times with 100 ml of ether each, the united extracts are dried over magnesium sulfate and the solvent and the traces of diethyl malonate are removed. The slightly yellow oil thus obtained slowly solidifies. Thus 41.8 g of the desired compound are obtained, yield 89%, mp.: 46°-50° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH2:18][CH2:19]Br>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:19][CH2:18][O:17][CH3:16]
Reactant: COCCBr
Reactant: Oc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOc1ccc(F)cc1Br
Yield: 65.8 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (1.2 g, 6.28 mmol) in acetonitrile (10 ml) was added potassium carbonate (2.78 g, 20 mmol) and 2-bromoethyl methyl ether (0.85 ml, 9.5 mmol). The resultant solution was heated to reflux for 16 hours. The reaction mixture was cooled then concentrated in vacuo. tert-Butyl-dimethyl ether (20 ml) and sodium hydroxide (1M aqueous solution) (10 ml) were added and the layers were separated. The organic layer was washed with saturated brine solution (10 ml) then dried over anhydrous Na2SO4 (s), filtered and evaporated in vacuo. Purification by column chromatography on silica gel eluting with heptane to heptane:ethyl acetate (9:1) afforded the title compound as a colourless oil (1.03 g, 66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH:7]=O.Cl.[NH2:14]O>C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[C:7]#[N:14]
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: NO
Agent: Cl
Solvent: O=CO
Product: CCOc1ccc(Br)cc1C#N
Temperature: 25 °C
Yield: 93.6 %

Procedure:
In formic acid (85.5 ml) was dissolved 5-bromo-2-ethoxybenzaldehyde (17.1 g). To the mixture was added hydroxylamine hydrochloride (7.8 g), and the mixture was refluxed for 7 hours and cooled to room temperature. Under reduced pressure, the solvent was evaporated, and the residue was washed with water and dried to give 5-bromo-2-ethoxybenzonitrile (15.8 g).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N:19]1([C:24]2[CH:30]=[CH:29][C:27](N)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[N:19]1([C:24]2[CH:30]=[CH:29][C:27]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(N2CCCC2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(N5CCCC5)cc4)c3c2s1
Yield: 48 %

Procedure:
Prepared from VII and 4-(pyrrolidin-1-yl)aniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 48%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3303, 2842, 2233, 1709, 1629, 1613, 1583, 1522, 1466, 1388, 1347, 1275, 1219, 1185, 1166, 1060, 1014, 989, 828, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.88 (d, 1H, J=9.0 Hz), 7.35 (d, 2H, J=8.1 Hz), 6.73 (d, 2H, J=8.1 Hz), 3.17 (m, 4H), 1.99 (m, 4H); HRMS calcd for C20H17N6S (M+H+): 373.1235, found 373.1218.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[CH:5]=1.[H-].[Na+].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>COC>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]1=2
Reactant: FC(F)(F)OC1=Cc2ccccc2Nc2ccccc21
Reactant: CN(C)CCCCl
Agent: COC
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C=C(OC(F)(F)F)c2ccccc21

Procedure:
10-Trifluoromethoxy-5H-dibenz[b,f]azepine (650 mg) was refluxed with NaH (600 mg, 57% suspension) in a solution of 3-dimethylaminopropyl chloride (ca. 2.0 g) in dimethyl ether (70 ml) overnight. The excess of NaH was destroyed with MeOH (10 ml) and the solvent removed under vacuum. The remaining gum was dissolved in ether (50 ml), washed with water (2×20 ml) and extracted into 2 N H2SO4 (2×20 ml). The extracts were combined, neutralized with NaHCO3 and extracted with ether (3×20 mls). The ether extracts were washed with water (2×20 mls), dried (Na2SO4) and the ether removed under vacuum.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH2:6])=[S:5])[CH3:2].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[CH2:1]([NH:3][C:4]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1)[CH3:2]
Reactant: CCNC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 42 was repeated but using 10 g of ethylthiourea, 20 g of ethyl bromopyruvate and 100 ml of ethanol, giving the title compound as a pale yellow powder.