Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][CH:4]=[C:3]([Cl:8])[CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:13](Cl)(=[O:15])[CH3:14]>O>[CH3:14][C:13]([C:4]1[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=1[Cl:8])=[O:15]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1cc(Cl)ccc1Cl
Temperature: 110 °C
Reaction time: 7 h

Procedure:
147 g (1.0 mol) of p-dichlorobenzene are completely melted at 60° C. in an apparatus having an attached dropping funnel, stirrer and reflux condenser. 120 g (0.9 mol) of anhydrous AlCl3 are added to the melt. 39.3 g (0.5 mol) of acetyl chloride are then added dropwise to the readily stirrable suspension at 60° C. in the course of about 1 hour, a clear solution slowly resulting. After heating to 110° C., the mixture is stirred at this temperature for 7 hours. After cooling to room temperature, the brown reaction mass is hydrolysed by cautious decantation onto a mixture of 200 ml of water and 200 g of ice. The temperature of the mixture is kept between 30 and 40° C. during the hydrolysis by external cooling. After separation of the phases, the lower, organic phase is washed with 400 ml of water and, after fresh phase separation, subjected to fractional distillation. The aqueous phases are discarded.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[CH:11]=[CH:10]2)[C:7](=[O:18])[N:6]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([NH:4][C:5]1[CH:17]=[CH:16][N:8]([C@@H:9]2[O:15][C@H:12]([CH2:13][OH:14])[CH2:11][CH2:10]2)[C:7](=[O:18])[N:6]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)n1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Yield: 77.7 %

Procedure:
A solution of 33 (0.78 g, 3.1 mmol) in ethanol (100 mL) was hydrogenated under 15 psi of hydrogen gas in the presence of 10% Pd/C (0.15 g) for 12 hours. The reaction mixture was filtered, concentrated, and the residue was purified by chromatography over silica using 5% methanol in CHCl3 as the eluent to obtain 0.61 g (77.5%) of 34 as a colorless solid: mp 143°-145° C. (benzene-methanol); 1H NMR (DMSO-d6) δ 1.60-2.50 (7H, m, 2',3'-H and COCH3), 3.40-3.85 (2H, m, 5'-H), 3.90-4.30 (1H, m, 4'-H), 5.07 (1H, t, J=5.0 Hz, OH), 5.91 (1H, m, 1'-H), 7.17 (1H, d, J=7.6 Hz, 5-H), 8.32 (1H, d, J=7.3 Hz, 6-H), 10.80 (1H, s, NH).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:21])([CH3:20])[C:18]#[N:19])=[CH:15][CH:16]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2nc(Cl)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-2,4-dichloropyrimidine (1.37 gm, 6 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (0.96 gm, 6 mmol) and diisopropyl ethylamine (1.6 mL, 9 mmol) were combined in 30 ml acetonitrile and stirred for 16 hr at RT. LC/MS at 16 hr indicated reaction was complete. Organics were washed sequentially with 1M citric acid solution, water, then brine. Organics were dried over sodium sulfate then decanted and evaporated to yield a crude material which was carried on as-is in the next step. (1.45 gm, 69%). MS m/z 353.3 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:17]2[CH:18]=[CH:19][C:14]([I:13])=[CH:15][CH:16]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(CO)c(C)o1
Reactant: Oc1ccc(I)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Yield: 63.4 %

Procedure:
A solution of 4-hydroxymethyl-5-methyl-furan-2-carboxylic acid methyl ester (16) (1.14 g) in tetrahydrofuran (15 mL) was cooled to 0° C. with stirring and treated with 4-iodophenol (4.6 g), triphenylphosphine (5.5 g) and diisopropylazodicarboxylate (4.2 g). After 10 minutes the cooling bath was removed. After 3 hours the reaction mixture was concentrated in vacuo and taken up in ethyl acetate (100 mL) and washed successively with water (100 mL), 1.0 M aqueous sodium hydroxide solution (100 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4 by volume) to give compound 20 as a white solid (1.58 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)=[C:15]3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:33])[NH:14][C:15]=23)[CH2:31][CH2:32]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f9) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O=S(Cl)Cl.[S:5]1[C:9]2[CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH3:18]O>>[CH3:18][O:16][C:15](=[O:17])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][S:5][C:9]=2[CH:10]=1
Reactant: O=C(O)Cc1ccc2ncsc2c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
SOCl2 (13.5 g, 114.0 mmol) was added dropwise to a stirred solution of benzothiazol-6-yl-acetic acid (20.0 g, 103.6 mmol) in 150 ml of methanol at 0° C. under N2. After stirring for 2 hours at room temperature the solvent was evaporated and the residue was diluted with ethyl acetate (150 ml). The mixture was washed with saturated sodium carbonate solution (100 ml×3) and brine (100 ml) and then concentrated in vacuo. The residue was purified by column chromatoghaphy eluting with ethyl acetate/petroleum ether (1:5) to return the title compound as a pale yellow oil (15.0 g, 71.5%).
Reaction SMILES: I[C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>>[CH3:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: C1CNCCN1
Reactant: Cc1cnc(I)s1
Product: Cc1cnc(N2CCNCC2)s1
Yield: 32 %

Procedure:
Prepared in analogy to example 2 (b) from 2-iodo-5-methyl-thiazole and piperazine. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow oil (yield 32%). MS (m/e): 184.3 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:13])[CH:9]=[CH:8]2.[Br:14]Br>>[Br:14][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11]2
Reactant: BrBr
Reactant: COc1cccc2ccc(C)nc12
Product: COc1ccc(Br)c2ccc(C)nc12
Yield: 86.6 %

Procedure:
Prepared using the same procedure described in Example 78 from 8-methoxy-2-methyl-quinoline [CAS 3033-80-5] (1.21 g, 6.96 mmol) and bromine (1.35 g, 8.42 mmol) to afford titled compound as a yellow solid (1.52 g, 86%). 1H NMR (DMSO-d6) 8.30 (d. J=8.4, 1H), 7.76 (d. J=8.4, 1H), 7.57 (d. J=8.4, 1H), 7.10 (d. J=8.4, 1H), 3.93 (s, 3H), 2.66 (s, 3H). LC/MS (Method B) 2.07 min, [M+1]+ 252/254.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][C:23]([OH:25])=[O:24])=[O:34])(=[O:11])=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)CS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a solution of ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid (44 mg, 0.11 mmol) in CH2Cl2 (2 ml) and acetonitrile (2 ml) was added mCPBA (27 mg, ˜0.11 mmol). The reaction was stirred at room temperature for 4 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 20-30% MeOH in EtOAc) followed by PTLC (25% MeOH in EtOAc) to yield the title compound (34 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:13]=[C:12]([NH:14][C:15](=[O:32])[C@@H:16]([NH:24]C(=O)OC(C)(C)C)[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:11]([CH3:33])[N:10]=2)[CH:6]=[CH:5][N:4]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][C:12]1[N:11]([CH3:33])[N:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:13]=1)=[O:32]
Reactant: COc1cc(-c2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)n(C)n2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cc(NC(=O)[C@@H](N)Cc3ccccc3)n(C)n2)ccn1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.7 %

Procedure:
To a 50 ml flask was added tert-butyl (S)-1-(3-(2-methoxypyridin-4-yl)-1-methyl-1H-pyrazol-5-ylamino)-1-oxo-3-phenylpropan-2-ylcarbamate 105.1.D (0.99 g, 2.19 mmole) and 20 ml of dichloromethane. To the solution, 5 ml of trifluoroacetic acid was added. The reaction was stirred at room temperature for 2.5 hours at which time the solvent was removed by rotary evaporation. The residue was suspended in ethyl acetate, and washed successively with saturated sodium bicarbonate, water and brine. The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give 105.1.E (706 mg, 92% yield) as yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][CH:13]([CH3:15])[CH3:14]>>[C:1]([C:5]1[O:9][N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7](=[NH:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CBr
Reactant: CC(C)(C)c1cc(N)no1
Product: CC(C)Cn1oc(C(C)(C)C)cc1=N
Temperature: 85 °C
Reaction time: 70 h
Yield: 61.9 %

Procedure:
A mixture of 5-tert-butylisoxazol-3-amine (3.0 g, 21 mmol) and 1-bromo-2-methylpropane (3.5 mL, 32 mmol) was warmed to 85° C. and was allowed to stir for 70 h. The mixture was cooled to ambient temperature and was purified by column chromatography (silica gel, 60% hexanes/EtOAc) to give the title compound (2.5 g, 13 mmol, 60% yield). MS (DCI/NH3) m/z 197 (M+H)+.
Reaction SMILES: [Cl:1][C:2](OC1C=CC(Cl)=CC=1)=[CH:3][C:4]([CH3:16])([CH3:15])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([OH:27])C>Cl>[Cl:1][CH2:2][C:3](=[O:27])[C:4]([CH3:16])([CH3:15])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: CCO
Reactant: CC(C)(C=C(Cl)Oc1ccc(Cl)cc1)CCOc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)(CCOc1ccc(Cl)cc1)C(=O)CCl
Yield: 88 %

Procedure:
580 g (1.5 mols) of 1-chloro-3,3-dimethyl-1,5-di-(4-chlorophenoxy)-1-pentene in 1,000 ml of ethanol and 300 ml of concentrated hydrochloric acid are heated under reflux for 4 hours. The ethanol is removed in vacuo, and the residue is diluted with methylene chloride and extracted by shaking with water, and then three times with dilute sodium hydroxide solution. The dried solution is freed of solvent in vacuo. 363 g (88% of theory) of 1-chloro-5-(4-chlorophenoxy)-3,3-dimethyl-2-pentanone are obtained as an oil.
Reaction SMILES: [Si](O[C@@H](CC)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH3:36])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1>>[NH2:25][CH2:26][CH2:27][CH2:28][C@@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH2:36][CH3:2])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Product: CC[C@H](OC)C(=O)N1N=C(c2cc(F)ccc2F)S[C@]1(CCCN)c1ccccc1

Procedure:
Prepared as in Example 71 using (S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 3H), 7.36 (app t, 2H, J=8 Hz), 7.13 (m, 2H), 4.54 (dd, 1H, J=8 Hz, 4 Hz), 3.31 (s, 3H), 3.23 (m, 1H), 2.84 (m, 2H), 2.44 (m, 1H), 1.94 (m, 2H), 1.78 (m, 1H), 1.48 (m, 1H), 1.08 (t, 3H, J=7 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH2:32][C:33](O)=[O:34])[CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH:18][C:33](=[O:34])[CH2:32][C:24]2[CH:25]=[CH:26][C:27]([C:28]([F:29])([F:30])[F:31])=[C:22]([F:21])[CH:23]=2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (175 mg, 0.000638 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (210 mg, 0.00096 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (610 mg, 0.0016 mol), N,N-diisopropylethylamine (0.28 mL, 0.0016 mol) and N,N-dimethylformamide (8 mL, 0.1 mol) and the reaction stirred at 45° C. for 24 hours. The reaction did not go to completion. The reaction was then quenched with water and extracted with ethyl acetate, washed with NaHCO3, brine and dried. The solvent was removed under reduced pressure and the residue purified by flash chromatography to obtain the product as a light yellow oil. MS m/z=479.3 (M+H)
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.CS([C:24]1[N:29]=[CH:28][C:27]2=[CH:30][CH:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[N:26]2[N:25]=1)=O>>[CH3:42][S:39]([C:36]1[CH:37]=[CH:38][C:33]([C:32]2[N:26]3[C:27]([CH:28]=[N:29][C:24]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:25]3)=[CH:30][CH:31]=2)=[CH:34][CH:35]=1)(=[O:41])=[O:40]
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Product: CS(=O)(=O)c1ccc(-c2ccc3cnc(-n4cnc5cnccc54)nn23)cc1

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine to afford 16.33 mg of 1-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=391.6. 1H NMR (400 MHz, DMSO, d6) δ 9.53 (m, 3H), 8.81 (m, 1H), 8.62 (d, 1H, J=6.32 Hz), 8.54 (m, 2H), 8.18 (m, 2H), 7.81 (d, 1H, J=4.92 Hz), 7.46 (d, 1H, J=4.93 Hz), 2.50 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Cl:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(n2c(Cl)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (850 mg, 1.92 mmol) in dry N,N-dimethylformamide (5 mL) was maintained at 95° C. while N-chlorosuccinimide (760 mg) was added in portions over 3 hours. Heating was continued for a total of 6 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound was eluted with ethyl acetate:hexanes/3:7 as a yellow solid (160 mg, 17%), 1H-NMR consistent with structure and almost identical with that of title compound of Example 3.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1.C1(C)C=CC(S(O[CH2:22][CH2:23][O:24][CH2:25][CH3:26])(=O)=O)=CC=1>CO>[CH2:23]([O:24][CH2:25][CH2:26][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1)[CH3:22]
Reactant: Cc1ccc(O)cn1
Reactant: CCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOCCOc1ccc(C)nc1
Reaction time: 0.08 h

Procedure:
A solution of 994 g (18.4 mmol) of sodium methylate in 20 ml of abs. methanol is added dropwise to a solution of 2 g (18.4 mmol) of 5-hydroxy-2-methylpyridine in 20 ml of abs. methanol. The mixture is stirred for 5 minutes and then a solution of 5.83 g (23.9 mmol) of (2-ethoxy)ethyl p-toluenesulphonate in 15 ml of abs. methanol is added. The mixture is heated under reflux for 72 hours. It is evaporated to dryness, the residue is taken up in ethyl acetate and washed with saturated NaCl solution. Drying over sodium sulphate and evaporation result in 2.1 g (70% of theory) of a pale yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH:13]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:14][CH:15]=[CH2:16])=[CH:10][CH:9]=1.C1C[O:30]CC1>CCOCC>[OH:30][CH2:16][CH2:15][CH2:14][CH:13]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[O:12][C:11]1[CH:25]=[CH:26][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1
Reactant: C1CCOC1
Reactant: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Solvent: CCOCC
Product: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4-{1-[4-(Tetrahydro-2H-pyran-2-yloxy)phenoxy]-3-butenyl}benzonitrile (from step (i) above; 4.6 g; 13 mmol) was dissolved in dry THF (50 mL) under argon and cooled to −5° C. Borane-methylsulfide complex (BH3xSMe2) (3.5 mL of a 2 M solution in ether) was added dropwise at 0 to 5° C. The mixture was stirred at that temperature for 1.5 h. After 4 h at rt, tlc showed that the reaction was complete. The reaction mixture was quenched with 14 mL of H2O and 5 g of NaBO3. The mixture was stirred overnight, the solvent decanted off, and the residue treated with ether and decanted. The combined organic fractions were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography on silica (iso-propanol:ethyl acetate:heptane; 5:20:70). Yield: 2.44 g (58%).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].[C:33](Cl)(=[O:43])[O:34][CH:35]([Cl:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CC1CCCO1.C(OCC)(=O)C>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:33]([O:34][CH:35]([Cl:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[O:43])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)OC(Cl)c1ccccc1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OC(Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of aripiprazole (1 g, 2.23 mmol) in 2-methyltetrahydrofuran (20 mL) was added NaH (178 mg, 4.46 mmol). The reaction was heated to reflux for 1.5 hours then cooled to room temperature. Chloro(phenyl)methyl carbonochloridate (1.37 g, 6.69 mmol) was then added and the reaction stirred overnight at room temperature. The reaction was cooled to 0° C., diluted with ethyl acetate (20 mL) and quenched with aqueous saturated NaHCO3 (20 mL) solution. The reaction was extracted with ethyl acetate (3×20 mL) and the combined organics washed with brine (50 mL), then dried (MgSO4) and concentrated to give chloro(phenyl)methyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 2.10 g) as a 1:3 mixture of product/aripiprazole. The product was taken onto the next step crude.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:3]1([N:8]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Product: CCCCCCCCCCCCCc1nc2ccccc2n1-c1ccccc1
Yield: 85 %

Procedure:
The title compound was prepared with the analogous procedure described in example 1 using 1-Iodo-2-nitrobenzene (125 mg, 0.5 mmol) and myristanilide (182 mg, 0.6 mmol) as starting materials to yield the title compound as colorless oil (160 mg, 85%). 1H NMR (DMSO) δ 0.74 (t, J=6.9 Hz, 3 H), 1.14-1.28 (m, 20 H), 1.68 (p, J=7.6 Hz, 2 H), 2.83 (t, J=7.6 Hz, 2 H), 7.14 (d, J=8.1 Hz, 1 H), 7.29 (dd, J=8.1, 7.7 Hz, 1 H), 7.47 (dd, J=8.1, 7.7 Hz, 1 H), 7.56-7.68 (m, 5 H), 7.74 (d, J=7.7 Hz, 1 H); 13C NMR δ 13.9, 22.0, 26.3, 26.4, 28.3, 28.4, 28.7, 28.8, 28.9, 29.9, 31.2, 110.7, 116.9, 123.5, 123.7, 127.2, 129.6, 130.1, 134.2, 135.0, 137.6, 154.7. HRMS (FAB): cal. for C26H36N2 [M+H+]: 377.2957; found: 377.2953.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH2:24]([N:26]([CH2:38][CH3:39])[CH2:27][C:28]#[C:29][CH2:30][NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1)[CH3:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][CH2:30][C:29]#[C:28][CH2:27][N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:8][CH2:7]1
Reactant: CCN(CC)CC#CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCN(CC)CC#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (780 mg) in 2-propanol (5 mL) were added 4-{[4-(diethylamino)but-2-yn-1-yl]amino}-1,3-thiazol-2(5H)-one (550 mg) and piperidinium acetate (334 mg) at room temperature. The reaction mixture was stirred at 60° C. for 3 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (640 mg).