Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1>ClCCl>[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NN=C(c2ccc(NC(=O)C(C)(C)C)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
1.56 ml (11.2 mmol) of triethylamine and 1.38 ml (11.2 mmol) of pivaloyl chloride were added to a solution of 3 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 160 ml of dichloromethane and the reaction mixture was stirred at 25° C. for one hour. The precipitate formed was filtered, washed with 3×5 ml of dichloromethane, then with 3×20 ml of water and dried to yield 1.59 g of pure product, m.p. 225°-227° C. (decomp.). The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3×20 ml of water, then with 3×15 ml of 4% aqueous sodium hydroxide solution, finally with 2×30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure. The crystalline residue was combined with the former product of 1.59 g and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3×3 ml of ethanol and dried to yield 3.38 g (87.8 %) of the pure product, m.p.: 225°-227° C. (decomp.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1
Reactant: OCCBr
Reactant: CC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.9 %

Procedure:
A mixture of 4-methylpiperidine (10 g, 0.10 mol), 2-bromoethanol (12.5 g, 0.10 mol), and triethylamine (15 g, 0.15 mol) in CHCl3 (100 mL) was stirred at room temperature for two days. The mixture was concentrated, and the residue was purified on a silica gel column (eluting with NH3—H2O/MeOH/DCM=1/6/300) to give 2-(4-methylpiperidin-1-yl)ethanol (3 g) as a colorless oil. 1H NMR (CDCl3): δ 3.57 (m, 2H), 3.24 (br s, 1H), 2.84 (m, 2H), 2.47 (m, 2H), 2.00 (dt, 2H), 1.58 (m, 2H), 1.35 (m, 1H), 1.21 (dt, 2H), 0.89 (d, 3H); LCMS: 144 (M+H)+.
Reaction SMILES: [CH3:1]/[C:2](/[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:3]\[CH2:4][OH:5].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:45]([O:47][C@@H:48]([CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH3:46]>C1C=CC=CC=1>[CH2:52]([O:51][C:49](=[O:50])[C@@H:48]([O:47][CH2:45][CH3:46])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[C:6]#[C:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:57][CH:56]=1)[CH3:53]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(C#Cc1ccccc1)=C\CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)C#Cc2ccccc2)cc1)OCC
Yield: 70.3 %

Procedure:
The title compound was prepared from of (E)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 g, 1.0 mmol), (J. Med. Chem. 1998, 41(14), 2524-2536), tributylphosphine (0.370 mL, 1.5 mmol), 1,1′-(azodicarbonyl)dipiperidine (0.378 g, 1.5 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL) by a procedure analogous to that described in example 3, yielding 0.276 g (68%) of (E)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3) δ: 1.1-1.25 (6H, m), 1.98 (3H, d), 2.95 (2H, d), 3.29-3.4 (1H, m), 3.53-3.65 (1H, m), 3.95 (1H, t), 4.15 (2H, q), 4.60 (2H, dd), 6.15 (1H, dt), 6.8 (2H, d), 7.15 (2H, d), 7.20-7.3 (3H, m), 7.35-7.45 (2H, m).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].[CH3:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH2:16]Br)=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH2:16][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COc1cc(CBr)c([N+](=O)[O-])cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cn2cccc2C=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a suspension of sodium hydride (0.724 g, 60% suspension in oil) in N,N-dimethyl formamide (50 mL) was added pyrrole 2-carboxaldehyde (1.7 g, 18.1 mmol) and the reaction mixture was stirred for 30 minutes. It was then cooled to 0° C. and 4,5-dimethoxy-2-nitrobenzyl bromide (5.0 g, 1 equiv) was added dropwise over 20 minutes. After the addition, the reaction mixture was stirred at room temperature for 3 hours. It was then diluted with ethyl acetate (450 mL), washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was triturated with water, filtered and washed with water. This material was dried over anhydrous potassium carbonate in vacuo to provide the title compound as a yellow crystalline solid (4.97 g), m.p. 109–112° C., which was used in the next step.
Reaction SMILES: [NH:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:14]([CH2:20][C:21]#[N:22])(=O)[C:15]([CH3:18])([CH3:17])[CH3:16]>>[C:15]([C:14]1[CH:20]=[C:21]([NH2:22])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][CH:13]=2)[N:2]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)c1ccc(NN)cc1
Product: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1

Procedure:
Ethyl 4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from ethyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O>ClCCCl.[O-2].[O-2].[Mn+4]>[OH:6][C@@H:5]([CH2:4][CH2:3][CH2:7][CH2:8][CH3:1])[CH2:7][CH2:8][CH2:1][C:5](=[O:6])[CH:4]=[CH2:3]
Reactant: Oc1ccc(O)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: C=CC(=O)CCC[C@@H](O)CCCCC

Procedure:
A solution of 5.22 grams of the diol in 1,2-dichloroethane was stirred with 63 grams of manganese dioxide in the presence of 50 milligrams of hydroquinone for one hour. After filtration to remove the manganese dioxide, washing with additional dichloroethane and ether, and evaporation of the filtrate at 30°C., there was obtained 3.98 grams of optically active 7(S)-hydroxy-1-dodecen-3-one.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([NH:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[C:38]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:13]3[CH2:14][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:11](=[O:25])[N:12]3[CH:22]([CH3:24])[CH3:23])[CH:16]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 3-tert-butylsulfamoyl-benzeneboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 3′-(1-benzenesulfonyl-3-isopropyl-2-oxo-imidazolidin-4-yl)-biphenyl-3-sulfonic acid tert-butylamide as an off-white oil. MS: 572.8 ([M+NH4]+)
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>C(O)(=O)C>[CH2:32]([N:35]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 39 h
Yield: 24.3 %

Procedure:
A solution of 3.12 g (0.010 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 39 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The brown residue was dissolved in 100 ml of THF, treated with 11.9 ml (0.0865 mol) of dipropylamine and stirred at room temperature for 22 hrs. The brown solution obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 1.0 g (24%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 123°-125°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:20]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([C:28]#[CH:29])[CH:27]=3)=[N:19][CH:18]=[N:17][C:9]2=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N#N.C(Cl)[Cl:33]>C(#N)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([Cl:33])=[C:22]([NH:21][C:20]2[C:8]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=3)[N:17]=[CH:18][N:19]=2)[CH:27]=1)#[CH:29]
Reactant: ClCCl
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Agent: N#N
Solvent: CC#N
Product: C#Cc1ccc(Cl)c(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Reaction time: 0.5 h

Procedure:
300 mg erlotinib was dissolved in 200 mL CH2Cl2 at −78° C. cooled by dry-ice/acetone bath. A mixture of F2 and N2 gas containing 20% F2/80% N2 was passed through the reaction vessel continuously at a flow rate of 2 L/min. Reaction was stopped after 30 min and the solvent was removed under vacuum. Dried reaction products were dissolved in 3 mL acetonitrile and was separated on an Agilent Zorbax C8 250×4.6 mm column, gradient elution from 30% MeOH/70% 0.1% formic acid in dd-H2O to 90% MeOH/10% 0.1% formic acid in dd-H2O, 1 ml/min total flow rate. Each fraction was analyzed by mass spectrometry. Fractions containing reaction products without excess amount of the starting material erlotinib, were mixed to form the modified erlotinib mixture compound library for drug property screening to identify components with improved properties over erlotinib. A component with m/z value corresponding to mono-chlorinated erlotinib was isolated and purified by successive preparative HPLC separations. The purified compound was analyzed by LC-MS/MS and NMR to provide the structure of the title compound. The observed m/z value 428.1371 (Thermo Finnigan LTQ Orbitrap, positive ion mode), is consistent with calculated m/z of protonated mono-chlorinated erlotinib (m/z(calc)=428.1372), molecular formula: C22H23ClN3O4+. High resolution MSn (n=2-4) experiments on LTQ orbitrap indicate the fluorine substitution is on the 3-ethynylphenyl ring of erlotinib (fragment at m/z 152.0262, calc: 152.0261 for C8H7ClN+). 1H-NMR spectra data indicate the chlorine substitution is at the 6-position of the 3-ethynylphenyl ring of erlotinib. 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.36 (s, 3H), 3.38 (s, 3H), 3.88 (m, 4H), 4.3-4.4 (m, 5H), 7.38 (s, 1H), 7.46 (dd, J=8.6, 2.7, 1H), 7.87 (d, J=8.6, 1H), 7.96 (d, J=2.7, 1H), 8.53 (s, 1H), 8.87 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][C@H:19]([CH3:32])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].Cl.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][C@H:19]([CH3:32])[CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])[C:5]([F:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: C[C@@H](N)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)Nc1nc(Cl)c(C#N)cc1F
Temperature: 60 °C
Yield: 29.2 %

Procedure:
2,6-dichloro-5-fluoro-3-pyridinecarbonitrile (3.3 g) and potassium carbonate (1.1 g) were added to a DMF (5 ml) solution containing (R)-2-(2-aminopropyl)isoindoline-1,3-dione•hydrochloride (690 mg), followed by stirring with heating at 60° C. for 5.5 hours. The reaction solution was adjusted to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=7:3, and a yellow solid of (R)-2-chloro-6-((1-(1,3-dioxoisoindolin-2-yl)propan-2-yl)amino)-5-fluoronicotinonitrile (300 mg) was thus obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@@H:3]([N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH:20]([O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[C:31]([CH:34]=O)[CH:30]=[CH:29]2)([CH3:22])[CH3:21]>>[F:19][C:2]([F:1])([F:18])[C@@H:3]([N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:34]([C:31]3[CH:30]=[CH:29][C:28]4[C:33](=[C:24]([O:23][CH:20]([CH3:22])[CH3:21])[CH:25]=[CH:26][CH:27]=4)[N:32]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Reactant: NNc1ccc([C@H](N2CC[C@@H](O)C2)C(F)(F)F)cn1
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@@H](O)C5)C(F)(F)F)cn34)nc12

Procedure:
Prepared as described in Example 9B, Steps A-F, using (R)-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ol in place of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate and using 8-isopropoxyquinoline-2-carbaldehyde in place of 8-methoxyquinoline-2-carbaldehyde in Step F. LCMS APCI (+) m/z 472.1 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:19][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH3:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(-c2cn3cc(I)ccc3n2)cc1
Reaction time: 5 h

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (820 mg) was dissolved in tetrahydrofuran (25 mL), and the solution was stirred under ice cooling. Methyl magnesium bromide (787 mL) was added dropwise to the reaction mixture, followed by stirring for 15 minutes under ice cooling and then for 5 hours at room temperature. Aqueous saturated ammonium chloride solution (25 mL) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane-methanol. Subsequently, the solvent was evaporated, and the residue was purified through silica gel column chromatography (dichloromethane:methanol=97:3), followed by concentration under reduced pressure, to thereby yield the title compound (579 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([OH:27])=O)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1>CN(C)C=O.O1CCCC1>[OH:49][C:46]1[CH:47]=[CH:48][C:43]([NH:42][C:25](=[O:27])[CH2:24][C@@H:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)=[CH:44][CH:45]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)Nc1ccc(O)cc1)c1nnc(C)n1-2
Temperature: -10 °C
Reaction time: 7.5 h
Yield: 16.8 %

Procedure:
(S)-4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (3.0 g) and triethylamine (1.2 ml) are added to a mixed solvent of dimethylformamide (30 ml) and tetrahydrofuran (15 ml). The mixture is cooled to -10° C., and pivaloyl chloride (1.0 ml) is dropwise added at said temperature. Thirty minutes later, a solution of 4-aminophenol (0.99 g) in dimethylformamide (20 ml) is dropwise added at said temperature, and the mixture is stirred at room temperature for 7.5 hours. After the completion of the reaction, tetrahydrofuran is distilled away, and saturated brine (200 ml) is added. The mixture is extracted with ethyl acetate, and the organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate: methanol=10:1) and crystallized from isopropyl alcohol to give 620 mg of (S)-N-(4-hydroxyphenyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide as pale-pink powdery crystals, melting point 215°-220° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:12]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(C(C)C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
14.7 g (0.10 mole) of p-methoxyphenylacetonitrile was dissolved in 250 ml of dry tetrahydrofuran and placed in a dry ice/isopropanol bath under N2. 69.0 ml of 1.6M n-butyl lithium (0.11 mole) was added dropwise over 30 minutes and the mixture stirred at -78° C. for one hour. The lithium salt of the nitrile precipitated as a yellow solid during this time. 71.0 g (0.50 mole) of methyl iodide was then added and stirring at -78° C. continued for an additional hour. The mixture was then poured into saturated ammonium chloride and the product extracted into diethyl ether, washed with saturated sodium chloride and dried over sodium sulfide. It was filtered and evaporated, redissolved in methylene chloride and passed through Florisel®. Evaporation gave 15.0 g of α-(p-methoxyphenyl)propionitrile as an orange oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(Cc1ccccc1Br)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-bromophenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.32 (dd, J=7.9, 1.3 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.97-8.01 (m, 1H), 7.90-7.93 (m, 1H), 7.64 (dd, J=7.9, 1.2 Hz, 1H), 7.53 (dd, J=7.6, 1.7 Hz, 1H), 7.39 (td, J=7.5, 1.3 Hz, 1H), 7.23-7.28 (m, 1H), 3.82-3.87 (m, 5H), 3.49-3.62 (m, 1H), 3.09-3.14 (m, 4H); MS (ESI+) M/Z 443 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C@@H:11]([C@@H:16]([CH3:21])/[CH:17]=[CH:18]\[CH:19]=[CH2:20])[C@@H:12]([CH3:15])[CH2:13][OH:14])=[CH:5][CH:4]=1.CS(C)=O.CCN(CC)CC.C(Cl)Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C@@H:11]([C@@H:16]([CH3:21])/[CH:17]=[CH:18]\[CH:19]=[CH2:20])[C@@H:12]([CH3:15])[CH:13]=[O:14])=[CH:7][CH:8]=1
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOCC
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)C=O
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of (2S,3S,4S,5Z)-3-[(4-methoxyphenyl)methoxy]-2,4-dimethyl-5,7-octadien-1-ol (2.0 g, 6.9 mmol), DMSO (2.1 mL), NEt3 (2.79 g, 27.59 mmol) and methylene chloride (20 mL) is cooled to 0° C., and is treated with SO3-Pyr (3.29 g, 20.69 mmol) and DMSO (8 mL) over 10 min. After additional 2 h at 0° C., the mixture is diluted with ether (200 mL), washed with 1 M aqueous NaHSO4 (100 mL), brine (100 mL), and concentrated. Flash chromatography (1% to 10% ethyl acetate in hexane) gives the desired compound (1.95 g, 98.2%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:33][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:15]([S:18]([CH:21]([CH3:22])[CH3:23])(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)C(C)C
Reactant: NC1CCCC1
Product: CC(C)S(=O)(=O)C(C#N)=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CCCC1
Yield: 99 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-isopropylsulfonyl-3-methylsulfanyl-2-propenenitrile (0.500 g, 1.16 mmol) was stirred in cyclopentylamine (2 ml) for 24 h at 80° C. under nitrogen in a sealed flask. Work up as described in Example 40, 2) gave 540 mg (99%) of the title compound as white crystals. Mp 172-173 ° C. 1H NMR (200 MHz, CDCl3): δ=1.41 (d, 6H), 1.40-1.57 (m, 4H), 1.74-1.93 (m, 4H), 3.25 (heptet, 1H), 3.56 (m, 1H), 7.54 (s, 2H), 7.67 (s, 1H), 7.94 (br s, 1H), 9.22 (br s, 1H)
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[Ca+2].O=[Si]=O.C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: O=C=O
Agent: O=[Si]=O
Agent: [Ca+2]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 200 °C
Yield: 90 %

Procedure:
p-Acetaminophenol 15 g, calcium carbonate 22.5 g, and quartz sand 67.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 4.0 MPa and heated to 200° C., maintained for 2 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve calcium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 98% and the yield is 90%.