Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:24])=[C:4]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].P(=O)(O)(O)O.[Cl-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:24])=[C:4]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCCCCCCCCCCC(O)c1c(O)c(Cl)cc(C=O)c1O
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCCCCCC=Cc1c(O)c(Cl)cc(C=O)c1O
Temperature: 25 °C
Yield: 83.6 %

Procedure:
5-Chloro-2,4-dihydroxy-3-(1-hydroxydodecyl) benzaldehyde (300 mg, 0.84 mmol) was stirred in acetic acid (2 ml) in the presence of 85% phosphoric acid (0.81 ml) at a reflux temperature for one hour. The reaction mixture was cooled to room temperature, added with a saturated sodium chloride solution (20 ml). After extractive workup with ethyl acetate, the crude product was purified by, silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5-chloro-3-(1-dodecenyl)-2,4-dihydroxybenzaldehyde (pale yellow solid 238 mg, yield 84%)
Reaction SMILES: Cl.[CH2:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH:3]=[CH2:4].C(Cl)Cl.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C(N(CC)CC)C>[CH2:2]([N:5]([C:21](=[O:22])[CH:20]([Cl:24])[Cl:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH:3]=[CH2:4]
Reactant: C=CCNc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C(=O)C(Cl)Cl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Twenty-three and eight tenths grams of N-allyl m-trifluoromethyl aniline hydrochloride was suspended in 200 ml. of methylene chloride, 21 g. of triethylamine was added and the mixture stirred in a water bath at room temperature while 15 g. of dichloroacetyl chloride was added dropwise. After stirring about 30 minutes, after addition was complete, the mixture was washed with dilute ~1% sodium hydroxide, dilute ~1% hydrochloric acid and water, separated and dried over magnesium sulfate and the solvent stripped under vacuum. The product was dissolved in ether and treated with 10 g. of 20% ethereal hydrochloric acid, the precipitate filtered off and the ether stripped under vacuum to give 25 g. of product, nD30 1.4740.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[N:13][N:12]([CH3:15])[C:11]=1[CH2:16][OH:17].Cl[C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][N:20]=1>CN(C=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]=[N:13][N:12]([CH3:15])[C:11]=1[CH2:16][O:17][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][N:20]=1
Reactant: Clc1ccc(I)cn1
Reactant: Cn1nnc(-c2ccccc2F)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(I)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a suspension of NaH (0.73 g, 18.1 mmol, 60% in mineral oil) in DMF (10 ml) under N2 atmosphere at 0° C. was added [5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-methanol (2.5 g, 12.06 mmol) and stirred for 1 h. Then 2-chloro-5-iodopyridine (3.17 g, 13.27 mmol) was added and reaction mixture was slowly warmed to room temperature and stirred for 4 h. The reaction was monitored by TLC. The reaction mixture was quenched with ice-water, extracted with ethylacetate (50 ml), washed with brine (10 ml), dried over Na2SO4 and concentrated under reduced pressure to afford crude mass (4.4 g, 88.9% mass balance). It was triturated with hexane and the solid was filtered and dried under vacuum to furnish 2-[5-(2-Fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-5-iodo-pyridine (2.4 g, 48.48%) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Br)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[NH:26][CH:27]=[CH:28][N:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:26]4[CH:27]=[CH:28][N:29]=[C:25]4[CH3:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ncc3O2)CC1
Product: Cc1nccn1-c1cc2c(cn1)OC(C1CCN(C(=O)OC(C)(C)C)CC1)C2

Procedure:
The title compound is prepared from 4-(5-bromo-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-methyl-1H-imidazole following a procedure analogous to that described in Example 69. LC (method 7): tR=1.22 min; Mass spectrum (ESI+): m/z=385 [M+H]+.
Reaction SMILES: [Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+].[Na+].[Na+].[Na+].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-][Si]([O-])=O.[Na+].[Na+]>>[Si:1]([OH:5])([OH:4])([OH:3])[OH:2].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: O=[Si]([O-])[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: O[Si](O)(O)O
Reaction time: 0.83 h

Procedure:
The said silicic acid gel, 25 parts by weight of phenol and 5 parts by weight of dry sodium metasilicate are mixed and heated to just below the boiling point of phenol while agitating for 25 to 75 minutes, thereby producing tan granules of phenol silicate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH:10]=[C:9]([O:13][CH3:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1.C([O-])(=O)C.[Na+].[I:22]Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([I:22])=[C:9]([O:13][CH3:14])[C:8](=[O:15])[NH:7][C:6]=2[CH:16]=1
Reactant: COc1cc(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.25 h

Procedure:
To a suspension of 8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (3.00 g) in glacial acetic acid (250 mL) was added sodium acetate (2.07 g) followed by iodine monochloride (15.2 mL). The mixture was heated to reflux for 1.5 hours, was allowed to cool, and the acetic acid was evaporated from the reaction mixture. The solid residue was suspended in tetrahydrofuran and stirred for 15 minutes. The solution was filtered and the resulting liltrate evaporated. The yellowish solid was recrystallized from refluxing toluene (700 mL) to afford the title compound (3.8 g); 250 MHz NMR: 11.60 (broad s, 1), 7.59 (d,1, J=7.1), 7.30 (d,1, J=1.4), 7.23 (dd,1, J=7.1, 1.6), 3.90 (s,3). Analysis for C11H7ClINO3 : Calculated: C, 36.34; H, 1.94; N, 3.85; Found: C, 36.35, H, 1.87; N, 3.82.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[CH:14]=[N:15][C:9]=2[CH:8]=1)(=O)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([NH:40][CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:33])([F:31])[F:32])[CH3:23])[CH:20]=4)[CH:14]=[N:15][C:9]=3[CH:8]=2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: C[C@@H](Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cc(CNC4CC4)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 58, 289 mg of crude [3-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (example 49, step 1) and 0.35 ml cyclopropylamine in 7 ml dichloromethane yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccnc4)cc32)N=C1N
Temperature: 120 °C
Yield: 90 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and pyridin-3-ylboronic acid (13 mg, 0.1 mmol). The mixture was heated under microwave at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-1′-methyl-2-phenyl-6-(pyridin-3-yl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (18 mg, 80%). 1H-NMR (MeOD): 2.39 (t, 1H), 2.52 (dd, 1H), 3.28 (s, 3H), 5.80 (d, 1H), 7.10 (d, 1H), 7.31 (m, 2H), 7.35 (m, 2H), 7.39 (m, 3H), 7.51 (s, 1H), 7.61 (m, 2H), 8.19 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[CH2:22]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]1[CH2:10][NH:11][CH2:12][C@H:13]1[OH:14])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N(Cc2ccccc2)Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@@H]1CNC[C@H]1N(Cc1ccccc1)Cc1ccccc1
Yield: 100.4 %

Procedure:
To tert-butyl (3R,4R)-3-(dibenzylamino)-4-hydroxy-pyrrolidine-1-carboxylate (350 mg, 0.91 mmol) synthesized in Reference Synthesis Example 71, 4 M hydrogen chloride/1,4-dioxane solution (3 mL) was added and the resultant solution was stirred at room temperature. The reaction solution was concentrated under reduced pressure and chloroform was added to the obtained residue, followed by washing the resultant mixture with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a crude product (258 mg) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:33]3[CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31][CH2:32]3)=[O:22])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Reactant: CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(CC)CC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.28 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 38 mg (0.33 mmoL) N-ethyl piperazine, 116 mg (0.30 mmol) HATU and 81 μL DIPEA in 1 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/MeOH-gradient. Yield: 36 mg (28%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].CC(C)([O-])C.[K+].[NH2:20]Cl>CN(C=O)C.CCOCC>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:20])[CH:9]=[CH:8]2)(=[O:4])=[O:3]
Reactant: NCl
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of 5-methanesulfonyl-1H-indole (4.1 mmol) and potassium tert-butoxide (8.2 mmol) in DMF (20 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (41 mL) is added drop-wise for 15 min at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 10% Na2S2O3 aqueous solution, and extracted with ether (3×40 mL). The combined organic layer is washed with water (2×30 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with EtOAc and heptane to afford 5-methanesulfonyl-indole-1-ylamine (230 mg, 32%) as a solid. MS: 211 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.08 (s, 3H), 4.94 (br, 2N—H), 6.55 (d, H), 7.34 (m, H), 7.57 (d, H), 7.73 (m, H), 8.21 (m, H).
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Mg]Br)C1C=CC=CC=1.[Cl:19][CH2:20][C:21](Cl)=[O:22].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:19][CH2:20][C:21]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: BrCc1ccccc1
Agent: Br[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CCl)Cc1ccccc1
Reaction time: 2.5 h

Procedure:
100 ml of anhydrous diethyl ether was added to 12.4 g of magnesium (used for the synthesis of a Grignard's reagent), to which were then added dropwise a mixture of 45 ml of benzyl bromide and 50 ml of an ether anhydride by using a dropping funnel over 30 minutes in a nitrogen atmosphere in a manner that the solution was mildly refluxed. This diethyl ether solution of benzylmagnesium bromide was added dropwise to a mixture of 40 ml of chloroacetyl chloride, 778 mg of cuprous iodide and 100 ml of tetrahydrofuran by using a dropping funnel over 2 hours in a nitrogen atmosphere such that the system temperature was kept at −60° C. After the addition was completed, the mixture was further stirred for 2.5 hours. Then, an aqueous saturated ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 1-3% ethyl acetate/hexane as an eluent for separation and purification, to give 20.4 g of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][C:19]=3[S:20][C:21]=2N(C)C)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[N:38]1([CH2:43][CH2:44][O:45][C:46]2[CH:51]=[CH:50][C:49]([Mg]Br)=[CH:48][CH:47]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:1][N:2]([CH3:37])[C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][C:19]=3[S:20][C:21]=2[C:49]2[CH:48]=[CH:47][C:46]([O:45][CH2:44][CH2:43][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:51][CH:50]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Br[Mg]c1ccc(OCCN2CCCC2)cc1
Reactant: CN(C)c1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Product: CN(C)c1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield by essentially following the procedures outlined in Example 81, Part E, from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-(dimethylamino)-4-(1-pyrrolidinylmethyl)phenyl ketone (Part F) and 4-[2-(1-pyrrolidinyl)ethoxy]phenyl magnesium bromide (Example 81, Part D).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([NH2:17])=[O:16])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:18]([C:21](Cl)=[O:22])[CH2:19][CH3:20]>>[C:21]([NH:17][C:15]([CH:13]1[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:6][C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:16])(=[O:22])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Cl
Reactant: NC(=O)C1c2ccccc2Oc2ccccc21
Product: CCCC(=O)NC(=O)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 222° C. and MS: m/e=295 (M+) was prepared in accordance with the general method of example 39 from 9H-xanthene-9-carboxylic acid amide and propanecarboxylic acid chloride.
Reaction SMILES: [Br:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]([O:6]C)=[O:5].CS(C)=O.[OH-].[Na+]>O>[Br:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
50.0 g (0.15 mol) of methyl 2-bromo-4-(4-chlorophenyl)nicotinate was weighed, and 300 ml of dimethylsulfoxide and 60 ml of 30% sodium hydroxide aqueous solution were added thereto and the mixture was stirred at 80° C. for 3 hours. The mixture was then poured into water and was washed with 300 ml of ethyl acetate. Thereafter, the aqueous layer was acidified with 10% HCl aqueous solution to precipitate a crystal, which was then filtrated out. The crystal thus precipitated was washed with water and isopropyl ether, and was dried to obtain 41.0 g of a white crystal of the aimed product.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([Br:12])[CH:5]=1)(=O)[CH3:2].[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:12][C:6]1[CH:5]=[C:4](/[C:1](=[N:19]/[S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH3:2])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9]
Reactant: CC(=O)c1ccc(C#N)c(Br)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C/C(=N\S(=O)C(C)(C)C)c1ccc(C#N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-acetyl-2-bromobenzonitrile (4.0 g, 18 mmol) and (S)-2-methylpropane-2-sulfinamide (2.4 g, 20 mmol) in THF (35 mL) was added titanium(IV) isopropoxide (8.1 mL, 36 mmol) and the reaction mixture was heated to 40 C under an atmosphere of nitrogen. After 2 hours, the reaction was cooled to room temperature, diluted in EtOAc, washed with saturated sodium bicarbonate, rochelle's salt, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography gave desired product. MS (M+H)+: observed=327.0/329.0, calculated=327.2/327.2.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([CH:29]([NH2:36])[CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])[CH3:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl.CO.C(N(CC)CC)C>[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]([CH:29]([NH:36][C:1]([C:4]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)=[O:28])[CH2:23][CH2:22]1)=[O:20])[CH3:17]
Reactant: COc1cc(C(=O)O)nc2ccccc12
Reactant: CCOC(=O)N1CCN(C(=O)C(N)Cc2c[nH]cn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)c2cc(OC)c3ccccc3n2)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq.), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1 M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%-6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCI (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%-6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10-3.30 (m, 2), 3.20-3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55-7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2].[NH2:32][CH2:33][CH2:34][CH2:35][OH:36]>O1CCOCC1>[C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2]
Reactant: NCCCO
Reactant: CS(=O)c1nccc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)n1
Solvent: C1COCCO1
Product: N#Cc1ccccc1Cn1cc(-c2ccnc(NCCCO)n2)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.1 %

Procedure:
A mixture of 70 mg of 1-(2-cyanobenzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 7(2)), 60.6 mg of 3-aminopropanol and 2 ml of dioxane was stirred at 80° C. for 5 hours. The reaction mixture was concentrated and then purified by silica gel column chromatography (chloroform: methanol=19:1) and crystallized from ether to give 44.6 mg of the title compound. Melting point: 166-167° C.