Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([O:24][CH3:25])[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]2[N:7]([C:15](=[O:23])[NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:6][CH2:5][C:4]=2[CH2:3]1.[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1[C:21]1[CH:22]=[C:17]([NH:16][C:15]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([O:24][CH3:25])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=3)[CH2:5][CH2:6]2)=[O:23])[CH:18]=[N:19][CH:20]=1
Reactant: Cc1ccncc1B(O)O
Reactant: COC1(Br)CC2=C(C=C1C(F)(F)F)N(C(=O)Nc1cccnc1)CC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cncc(-c3cnccc3C)c1)CC2
Yield: 66.7 %

Procedure:
1-[5-Bromo-(3-pyridylcarbamoyl]-5-methoxy-6-trifluoromethylindoline (D26) (0.3 g 0.7 mmoles) and 4-methyl-3-pyridylboronic acid (0.12 g, 0.9 mmoles) was heated under reflux in dimethoxyethane (80 ml) and water (10 ml) with sodium carbonate (0.15 g, 1.4 mmoles) and palladium tetrakis triphenylphosphine (0.1 g, 12 mole %) under an inert atmosphere for 18 hours. After cooling the mixture was partitioned between ethyl acetate (250 ml) and water (200 ml). The organic layer was separated and washed with saturated sodium chloride solution then dried (Na4SO4). Evaporation of the solvent followed by flash chromatography on silica gel eluting with 3-7% MeOH/CH2Cl2 and recrystallisation from ethyl acetate/60-80 petrol gave the title compound (E35) (0.2 g, 65%) m.p. 125-8° C.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:19])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:19][S:1](=[O:2])[O:5][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: NC(CC1=Cc2ccccc2CC1)=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1NC(CC2=Cc3ccccc3CC2)=NO1
Yield: 14.3 %

Procedure:
Thionyl chloride (2.55 mL, 0.035 mol) was added dropwise to a mixture of N'-hydroxy-(3,4-dihydro-2-naphthalenyl)ethanimidamide (6.5 g, 0.032 mol) and pyridine (5.18 mL, 0.064 mol) in dry CH2Cl2 (100 mL) at 0° C. After the addition, the reaction mixture was concentrated under reduced pressure, placed in an ice bath, diluted with water (50 mL), extracted with ether (3×50 mL), filtered, dried (MgSO4), and concentrated under reduced pressure to give a red brown solid. The solid was triturated three times with ether (50 mL) and recrystallized from ether (75 mL) to yield 1.14 g (14.4%) of pure product as tan crystals, m.p. 118°-120.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][CH2:23][C:24](=[O:25])[C:9]=23)[CH:5]=[CH:6][CH:7]=1.CO.C(Cl)Cl.[BH4-].[Na+]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[CH:16]=[C:15]([O:18][CH3:19])[CH:14]=[CH:13][C:12]=3[C:11](=[O:20])[N:10]3[CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(=O)CCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(O)CCC3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione in 5 mL 1:1 MeOH:CH2Cl2 was added NaBH4 (17 mg). The reaction was stirred at room temp for 1 h, then diluted with bicarb and EtOAc and stirred for 30 min. The mixture was extracted once with EtOAc, and the organic solution was washed once with brine, dried (Na2SO4) and concentrated. Flash chromtaography (40 g silica, 50-100% EtOAc/hexanes) gave the titled compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:27]([CH3:31])[C:28](=O)[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:17]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]2[O:25][C:27]([CH3:31])=[C:28]([CH3:29])[C:12]=2[CH:13]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)C(C)Cl
Reactant: O=C(Nc1ccc(O)c(NC(=O)c2ccccc2)c1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc2c(NC(=O)c3ccccc3)cc(NC(=O)c3ccccc3)cc2c1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A mixture of 2,4-bis(benzoylamino)phenol (6.0 g), 3-chlorobutan-2-one (2.3 g) and potassium carbonate (5.0 g) in N,N-dimethylformamide (30 ml) was stirred at 70° C. for 3 hours. The reaction mixture was cooled and poured into water. The separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. To the residue was added conc. sulfuric acid (30 ml) and the mixture was stirred at 40° C. for 7 hours. The reaction mixture was cooled and poured into a mixture of ice and water. The separated oil was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 5,7-bis(benzoylamino)-2,3-dimethylbenzo[b]furan (3.7 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]=O)=[CH:21][C:16]=2[CH2:15][CH2:14]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([CH:22]3[C:5]4[NH:6][C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]=4[CH2:3][CH2:2][NH:1]3)=[CH:21][C:16]=2[CH2:15][CH2:14]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)CCO2)NCC3
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
This product was prepared using a two-step procedure. A solution of tryptamine (32.4 g, 0.2 mol) and 2,3-dihydrobenzofuran-5-carboxaldehyde (30.0 g, 1 equiv.) in toluene (1 L) was heated under reflux for 4 hours. After removal of 4 mL of water and evaporation of toluene the residue was dissolved in DCM (1 L) in the presence of TFA (31 mL, 2 equiv.). The resulting mixture was stirred at rt for 16 hours. Then 1 L of a saturated aqueous solution of NaHCO3 was added. After extraction with DCM and drying over MgSO4, the organic solution was evaporated in vacuo. Recrystallization from DCM:iPr2O (2:30) gave the title compound as white crystals in a 80% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1O)OCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of 100 g of 2-hydroxyphenylacetic acid, 75 cm3 of benzyl alcohol and 0.5 g of paratoluenesulphonic acid in 1400 cm3 of toluene is refluxed for 2 hours while removing the water formed. After cooling, treating with 3 g of animal black and filtering, the reaction mixture is concentrated to 150 cm3 and 300 cm3 of isopropyl oxide are added. The crystals obtained by cooling to 0° C. are drained, washed and dried to give 82.5 g of benzyl 2-hydroxyphenylacetate. 174 g of potassium carbonate are added to a solution of 153 g of this ester in a mixture of 500 cm3 of 1,3-dibromopropane and 2500 cm3 of acetonitrile, and the mixture is refluxed for 17 hours. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 500 cm3 of ethyl acetate and the organic phase is washed with 400 cm3 of water twice and twice with 250 cm3 of a saturated solution of sodium chloride and then dried and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 9 cm, height 55 cm), eluting with a cyclohexane and ethyl acetate mixture (95/5 by volume) and collecting fractions of 500 cm3. Fractions 12 to 18 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 90 g of benzyl 2-(3-bromopropoxy)phenyl-acetate in the form of a yellow oil. A solution of 40 g of this product in 500 cm3 of acetonitrile is heated in an autoclave with 27 g of sodium iodide and 90 g of dimethylamine for 16 hours at 80° C. The reaction mixture is cooled, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by acid-base treatment to give 29.3 g of benzyl 2-(3-dimethylaminopropoxy)phenylacetate in the form of a yellow oil. Hydrogenation of this ester, at atmospheric pressure at 40° C. in ethyl acetate in the presence of palladium hydroxide followed by crystallization from ethyl acetate, yield 17.5 g of 2-(3-dimethylaminopropoxy)phenylacetic acid in the form of white crystals; melting point 98° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:28][CH3:29])=[N:18][N:19]3[C:24]([OH:25])=[CH:23][C:22]([CH2:26]Cl)=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:28][CH3:29])=[N:18][N:19]3[C:24]([OH:25])=[CH:23][C:22]([CH2:26][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:21][C:20]=23)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1COCCN1
Reactant: CSc1nn2c(O)cc(CCl)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(O)cc(CN3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
1 ml (6 mmol) of morpholine was added to a solution of 2.0 g (5.40 mmol) of 3-benzenesulphonyl-5-chloromethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 0.5N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 10:1) yielded 2.0 g (88%) of 3-benzenesulphonyl-2-methylsulphanyl-5-morpholin-4-ylmethyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige foam.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].ClCCl.[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc(CO)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (5 g, 20.4 mmol) was stirred in a 2:1 dichloromethane:MeOH solution (102 mL) and cooled to 0° C. The reaction was treated with sodium borohydride (0.309 g, 8.16 mmol), warmed to ambient temperature, and stirred for 20 hours. The mixture was quenched with a 10% sodium carbonate solution, extracted with dichloromethane (3×100 mL), and partitioned between water and dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford ethyl 1-(hydroxymethyl)-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-5 using tert-butyl 4-hydroxypiperidine-1-carboxylate and 4-bromophenol (0.65 g, 36%); MS: 256 (M−100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.Cl.[F:26][C:27]1([F:36])[CH2:32][C:31]([F:34])([F:33])[CH2:30][N:29]([NH2:35])[CH2:28]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:35][N:29]3[CH2:28][C:27]([F:26])([F:36])[CH2:32][C:31]([F:33])([F:34])[CH2:30]3)=[O:23])[C:9]=2[CH3:24])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CC(F)(F)CC(F)(F)C1
Agent: Cl
Product: Cc1c(C(=O)NN2CC(F)(F)CC(F)(F)C2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Form the acid chloride from 2.0 mmol of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid and react it with 1.4 mmol of the product of Example 33 using the general procedure set forth in Example 39, to yield the title compound as a white solid.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[I:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1N>ClCCl>[F:1][C:10]1[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=1[I:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A solution of nitrosonium tetrafluoroborate (24 g, 0.21 mol) in dichloromethane (200 mL) at 0° C. was treated with a solution of 2-iodo-4-nitroaniline (50 g, 0.19 mol) in dichloromethane (350 mL) and stirred at 0° C. for 1 h. The dichloromethane was concentrated to about half volume and the reaction mixture was treated with 1,2-dichlorobenzene (300 mL). The remaining dichloromethane was further concentrated in vacuo. The resultant 1,2-dichlorobenzene suspension was heated at 110° C. for 1 h, cooled to 20° C., and treated with water (200 mL) and dichloromethane (500 mL). The reaction mixture was filtered over celite and the celite was washed with dichloromethane and water. The aqueous layer of the filtrate was separated and extracted with dichloromethane (2×). The combined organic layers were washed with 20% sodium thiosulfate and brine, dried over anhydrous sodium sulfate, and filtered. The dichloromethane was removed under standard conditions while the 1,2-dichlorobenzene was removed via vacuum distillation to give a crude dark oil. This material was purified by distillation to give the desired product (19 g, 38%) as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][C:16]1([CH3:24])[O:20][C@H:19]([CH2:21][O:22][NH2:23])[CH2:18][O:17]1.C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][C@@H:19]2[CH2:18][O:17][C:16]([CH3:24])([CH3:15])[O:20]2)[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CC1(C)OC[C@@H](CON)O1
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](CONc2nc(NC=O)nc(Cl)c2NC=O)O1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (7.3 g, 31.1 mmol), (S)-2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamine (4.6 g, 31.1 mmol) and diisopropylethylamine (8.03 g, 62.1 mmol) in diglyme (125 ml) was stirred at 100° C. for 4 h. The reaction was filtered, evaporated and the residue chromatographed twice in chloroform-methanol 15:1 affording (S)-4-chloro-2,5-diformamido-6-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxyamino)pyrimidine(2.6 g, 24%). υmax (CHCl3) 3400, 1700, 1580, 1560 and 1470 cm-1 ; δH (CDCl3) 1.39(3H,S,CH3), 1.48(3H,S,CH3) , 3.60-4.65(5H,m,CH2ONH+CH2OCMe2 +CHOCMe2), 7.96(1H,br.m, D2O exchangeable, NH), 8.34(1H,S,CHO), 9.25(2H,br.m,D2O exchangeable, 2XNH) and 9.50(1H,S,CHO); m/z 344(M+ -H,<1%), 330(M+ -CH3, <1%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][C:9]2=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Fc1ccc(C2(c3ccc(F)cc3)CCNC2)cc1
Temperature: 25 °C

Procedure:
In a 500 mL flask containing 3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 58B, 4.1 g, 15 mmol) as a suspension in ether (300 mL) was added lithium aluminum hydride (2.0 Min tetrahydrofuran, 15 mL, 30 mmol) slowly via syringe under nitrogen. The reaction was refluxed overnight, cooled to room temperature, and then carefully quenched by the slow addition of 1 N NaOH (60 mL). The reaction was diluted with ethyl acetate (200 mL) and filtered through a pad of diatomaceous earth. The organic phase was separated, concentrated, and the residue purified over silica gel eluting with 97:3 dichloromethane/methanol to give the title compound. MS (DCI+) m/z 260 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=NN=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][C@@H:18]([N:20]([C:25]([C:27]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:30]3[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=3[N:28]=2)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][C@@H:16]([C:42](O)=[O:43])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C1CCC(N=C=NC2CCCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:30]2[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=2[N:28]=[C:27]1[C:25]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@H:18]1[CH2:17][C@@H:16]([C:42]2[O:43][C:2]([CH3:1])=[N:6][N:5]=2)[CH2:15][N:14]([C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13])[CH2:19]1)=[O:26]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: Cc1nnn[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnc(C)o3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
Methyltetrazole (63 mg) and (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg) were dissolved in toluene (5 ml), DCC (155 mg) was added and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, filtered and the solvent of the mother liquor was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH:30]2[CH2:32][CH2:31]2)([CH:27]2[CH2:29][CH2:28]2)[OH:26])=[CH:6][CH:5]=1.[CH3:33]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH:30]2[CH2:32][CH2:31]2)([CH:27]2[CH2:29][CH2:28]2)[O:26][CH3:33])=[CH:6][CH:5]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
Sodium hydride (60% in oil, 17.5 mg, 0.438 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](dicyclopropyl)methanol (100 mg, 0.216 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After stirring min, methyl iodide (61.3 mg, 0.422 mmol) was added to the mixture, and the mixture was stirred at room temperature for 6 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (59.4 mg, 0.125 mmol, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:12][O:13][CH3:14])=[CH:7][N:8]=1
Reactant: COc1ccc(O)cn1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(OC)nc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a solution of 6-methoxypyridin-3-ol (20 g, 0.16 mol) in DMF (200 mL) was added NaH (60% in mineral oil; 9.6 g, 0.24 mol) at 0-5° C. portion-wise. Upon the completion of addition, the mixture was continued to stir at 0-5° C. for 15 min followed by additional of chloromethyl methyl ether. The mixture was stirred at 0-5° C. for another 20 min and quenched with aqueous NH4Cl(sat). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)pyridine (24.1 g, 89.3%) as a colorless oil. 1H NMR (400 MHz; CDCl3) 7.97 (d, 1H), 7.35 (dd, 1H), 6.70 (d, 1H), 5.12 (s, 2H), 3.91 (s, 3H), 3.51 (s, 3H); MS (ESI) m/z 170.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.C1COCC1.[CH2:19]([S:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])[CH3:20].C(=O)([O-])O.[Na+]>O>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:24](=[O:25])[C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[S:21][CH2:19][CH3:20])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CCSc1ccccc1C(=O)Cl
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
To a mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine (3.82 g) and THF (40 ml), 2-ethylsulfanylbenzoic acid chloride (4.42 g) was added, stirred at 50° C. for 2 hours, then stirred under reflux for hours. After the mixture was allowed to cool to room temperature, sodium hydrogen carbonate (1.85 g) was added thereto, and stirred at 50° C. for 2 hours. After the mixture was allowed to cool to room temperature, water was poured thereinto, and then the precipitated solid was collected by the filtration. The resulting solid was washed with water and hexane, and dried to give 7.15 g of N-(2-methylamino-5-trifluoromethylpyridine-3-yl)-2-ethylsulfanyl-benzamide (Compound ((1B)-19).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:25][NH2:26])[CH:16]=1>>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH2:25][NH:26][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH:16]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1cnc2ccccc2c1
Product: COC(=O)c1ccc(S(=O)(=O)NCc2cnc3ccccc3c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and quinolin-3-ylmethanamine.