Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:14][C:15]=2Cl)=[CH:7][CH:6]=1.COC(NC1C=CC(B(O)O)=CC=1)=O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:1][O:2][C:3](=[O:33])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C@@H:17]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Nc1ccc(-c2nc([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)[nH]c2Cl)cc1
Agent: COC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Nc1ccc(-c2c[nH]c([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)n2)cc1
Temperature: 80 °C

Procedure:
{4-[2-((S)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-5-chloro-1H-imidazol-4-yl]-phenyl}-carbamic acid methyl ester: To 92E (4.5 g, 12.2 mmol) were added 4-(methoxycarbonylamino)-phenyl boronic acid (2.97 g, 15.0 mmol), and potassium carbonate (5 g, 36 mmol). To this mixture was added 4:1 DME/water (100 mL) that had been degassed with N2. Tetrakis[(triphenyl)phosphine]palladium (0.7 g, 0.61 mmol) was added and the reaction was heated at 80° C. for 24 h. The reaction was cooled and solvents removed in vacuo. The residue was partitioned with ethyl acetate/water and the layers separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration afforded {4-[2-((S)-1-tert-butoxycarbonylamino-2-phenyl-ethyl)-1H-imidazol-4-yl]-phenyl}-carbamic acid methyl ester as a yellow foam (8.1 g). LCMS m/z 437.02 (M+H)+. To this intermediate (5.3 g, 12.2 mmol) in acetonitrile (60 mL) was added N-chlorosuccinimide (1.8 g, 13.4 mmol), and the reaction was heated to 55° C. for 24 h. The solvent was removed in vacuo, the residue was partitioned with ethyl acetate/saturated aqueous sodium carbonate, and the layers separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried (MgSO4). Purification by silica gel chromatography (hexane/ethyl acetate) afforded 92F (1.92 g, 33.6% over 2 steps) as a yellow foam. LCMS m/z 471.3 (M+H)+. 1HNMR (400 MHz, CDCl3) δ: 1.39 (s, 9H), 3.30 (d, J=7.07 Hz, 2H,) 3.79 (s, 3H), 4.85 (d, J=7.58 Hz, 1H), 5.20 (d, J=7.58 Hz, 1H), 6.68 (s, 1H), 7.14-7.32 (m, 4H), 7.38-7.56 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8](Cl)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.BrC1C(C(O)=O)=NC=CC=1.S(Cl)(Cl)=O.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27]O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([C:8]2[O:9][CH2:27][C:26]([CH3:30])([CH3:29])[N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ncccc1Br
Reactant: CC(C)(N)CO
Agent: O=C(O)c1ncccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC1(C)COC(c2ncccc2Br)=N1

Procedure:
A solution of 5.0 g. of 3-bromopicolinoyl chloride (prepared by refluxing 3-bromopicolinic acid with thionyl chloride by the procedure of Example 2) in 25 ml. of dichloromethane is added to a solution of 3.9 g. of 2-amino-2-methylpropanol in 25 ml. of dichloromethane at 0°C. The resulting hydroxyalkylpicolinamide is cyclized by refluxing with thionyl chloride by the method of Leffler and Adams, J. Am. Chem. Soc. 59:2252 (1937) and the resulting hydrochloride salt is neutralized with aqueous sodium hydroxide solution to give 3-bromo-2-(4,4-dimethyl-2-oxazolinyl)pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][Cl:11])[CH:7]=[CH:6][C:5]=1[S:12][C:13]1[C:14](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16])([O-])=O>CO.[Ni].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][Cl:11])[CH:7]=[CH:6][C:5]=1[S:12][C:13]1[C:14](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccccc1Sc1ccc(CCl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccccc1Sc1ccc(CCl)cc1N
Reaction time: 17 h
Yield: 95.4 %

Procedure:
A solution of 9.0 g (27.8 mmol) of methyl S-(2-nitro-4-chloromethylphenyl)thiosalicylate in 100 mL of methanol was hydrogenated over Raney nickel (1.12 g) at room temperature and 30 psi pressure with stirring for 17 hours. The residue obtained on evaporation of the methanol was dissolved in chloroform, filtered, dried over MgSO4, filtered, and concentrated in vacuo to provide methyl S-(2-amino-4-chloromethylphenyl)thiosalicylate as a white solid (8.16 g, 55.6%), 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H, —OCH3), 4.40 (s, 2H, —NH2), 6.77 (dd, 1H, J=1.2 Hz), 6.79 (dd, 1H, J=2.1 Hz), 6.84 (dd, 1H, J=2.4 Hz), 7.15-7.20 (m, 1H), 7.28-7.34 (m, 1H), 7.40 (d, 1H, J=8.1 Hz), 8.006 (dd, 1H, J=1.5 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[CH2:24][NH:23][C:21]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([N:1]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([CH3:20])[CH3:19])=[O:22]
Reactant: BrCCCCBr
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N3CCCC3)cc2n1Cc1ccccn1
Temperature: 110 °C

Procedure:
To a solution of 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182, 64 mg, 0.15 mmol) in toluene (2 ml) was added 1,4-dibromobutane (19 μl, 0.16 mmol) and i-Pr2NEt (77 μl, 0.44 mmol). The reaction was heated at 110° C. for 16 h, and was purified directly by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@@:3]([CH2:17]SC1C=CC(C)=CC=1)([OH:16])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[CH3:15])([CH3:7])[CH3:6].F[B-](F)(F)F.C[O+](C)C.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>ClCCl.O>[F:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C@:3]2([C:2]([F:27])([F:26])[F:1])[CH2:17][O:16]2)[CH:13]=1
Reactant: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(F)ccc2C)C(F)(F)F)cc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77.6 %

Procedure:
To a solution of (S)-1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol (1.37 g, 3.41 mmol) in 10 mL of anhydrous dichloromethane was added trimethyloxonium tetrafluoroborate (757 mg, 5.12 mmol). The resulting suspension was stirred at room temperature for 4.5 hours. A solution of potassium carbonate (1.41 g, 10.2 mmol) in 10 mL of water was then added. After 19 hours, the reaction mixture was poured into 40 mL of saturated aqueous sodium bicarbonate solution and extracted with three 50 mL portions of dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography with silica gel (eluted with 0%-2% EtOAc-hexanes) afforded the title compound as a clear oil (731 mg, 78%).
Reaction SMILES: Br[C:2]1[C:3]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.[OH:26][CH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1>>[Cl:25][C:22]1[S:21][C:20]([C:3]2[C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=3)=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]3[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]3=[O:19])[N:4]=2)=[CH:24][CH:23]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2ccc(Cl)s2)n1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(CO)c2)c(-c2ccc(Cl)s2)n1

Procedure:
The title compound was prepared from 1-{2-[5-bromo-4-(5-chlorothiophen-2-yl)pyrimidin-2-ylamino]ethyl}-5,5-dimethylimidazolidine-2,4-dione and 3-(hydroxymethyl)phenylboronic acid in a manner analogous to Example 269. MS (M+H)+ 472.
Reaction SMILES: [N+]([NH:4][C:5]([NH2:7])=[O:6])([O-])=O.[N:8]1([CH2:14][CH2:15][O:16][CH:17]2[CH2:21][CH2:20]N[CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>C(O)C>[N:8]1([CH2:14][CH2:15][O:16][CH:17]2[CH2:21][CH2:20][N:4]([C:5]([NH2:7])=[O:6])[CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: C1CCN(CCOC2CCNC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)N1CCC(OCCN2CCCCC2)C1

Procedure:
Nitrourea (7.3 g., 0.055 mole of 80% wet reagent) and 3-(2-piperidinoethoxy)pyrrolidine were stirred together in 100 ml. ethanol at reflux for 2 hr. After cooling, the reaction mixture was filtered and the filtrate concentrated to give 12.5 g. solid material which was determined by nuclear magnetic resonance spectrum analysis to be a salt. The crude product was treated with dilute sodium hydroxide solution and the free base extracted into chloroform twice. The chloroform extracts were combined, washed with water, dried over magnesium sulfate, filtered, and concentrated to give 6.8 g. of off-white solid product. Recrystallization from isopropyl ether-isopropanol gave 3.7 g. (30.7%) white solid, m.p. 133.5°-135.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C:9](=[O:14])[C@@H:8]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24].[CH2:30]1COC[CH2:31]1>>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@:9]([C:30]#[CH:31])([OH:14])[C@@H:8]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24]
Reactant: C1CCOC1
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)C1=O
Product: C#C[C@]1(O)C(OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
To a cold (−20° C.) solution of (4R,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-dihydrofuran-3-one (9.16 g, 19.07 mmol,) in dry THF (20 mL) is added dropwise a solution of 0.5M alkynylmagnesium bromide (e.g. where R3=H, alkynylmagnesium bromide is ethynylmagnesium bromide) in THF (57.2 mL, 28.6 mmol). The yellow reaction mixture is stirred at the same temperature for 1 h and quenched with saturated NH4Cl (50 ml) and extracted with IPAC (2×70 mL). The organic layer is washed with water (50 mL), concentrated to give (3R,4R,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-3-ethynyl-2-methoxy-tetrahydrofuran-3-ol (I-4) (R3=H) as dark red oil which is directly used for the next step.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:80][C:81]1[CH:88]=[CH:87][C:84]([NH:85][CH3:86])=[CH:83][CH:82]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:80][C:81]1[CH:88]=[CH:87][C:84]([N:85]([CH3:86])[C:23]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]2)=[O:13])=[CH:22][CH:21]=3)=[O:24])=[CH:83][CH:82]=1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CNc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1)c1ccc(F)cc1
Yield: 44 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 34, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-fluoro-N-methylaniline (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a yellow solid (44%).
Reaction SMILES: CO[CH2:3][C:4]1[C:13]([F:14])=[C:12](F)[C:7]([C:8](OC)=[O:9])=[C:6]([S:16][CH3:17])[C:5]=1[F:18].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[F:18][C:5]1[C:6]([S:16][CH3:17])=[C:7]([CH:12]=[C:13]([F:14])[C:4]=1[CH3:3])[CH2:8][OH:9]
Reactant: COCc1c(F)c(F)c(C(=O)OC)c(SC)c1F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSc1c(CO)cc(F)c(C)c1F
Reaction time: 0.5 h
Yield: 105.8 %

Procedure:
Methyl 4-(methoxymethyl)-2-methylthio-3,5,6-trifluorobenzoate (0.48 g) was dissolved in dry tetrahydrofuran (2 cm3) under a nitrogen atmosphere at room temperature. To the stirred solution was added dropwise a solution of lithium aluminum hydride (1.0 cm3 of a 1.0 molar solution in THF). The mixture was stirred for 0.5 hour when stored for 18 hours. The solution was treated with 2 molar hydrochloric acid and extracted with dichloromethane (twice), dried (anhydrous magnesium sulphate), and evaporated under reduced pressure to give a pale yellow liquid (0.37 g). The liquid was fractionated by eluting through a bed of silica gel with dichloromethane/ethyl acetate (50:1 by volume) to yield the title product (0.04 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=O>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[C:13]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: Nc1ccccc1S
Product: COc1ccc(OC)c(-c2nc3ccccc3s2)c1

Procedure:
2-Aminothiophenol (6.3 g., 0.05 mole) and 8.3 g (0.05 mole) of 2,5-dimethoxybenzaldehyde were combined and mixed thoroughly. After a few minutes the mixture evolved heat, became cloudy, and slowly crystallized. The mixture was then warmed for a few minutes to complete the reaction. The product was then recrystallized from ethanol yielding 8.0 g (59%), mp. 96°-99°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:11]>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:10](=[O:11])[O:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: NCc1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: O=C(NCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of pyridin-4-ylmethanamine (505 uL, 5 mmol) and p-nitrophenyl chloroformate (1.0 g, 5 mmol) in dichloromethane (20 mL) was stirred at room temperature for 5 h. Upon completion, the product was collected by vacuum filtration, washed with dichloromethane and purified by preparative HPLC (10-90% acetonitrile in water) to provide 4-nitrophenyl pyridin-4-ylmethylcarbamate as a white solid. MS=274 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:13]=[CH:12][S:11][C:10]=2[C:14](O)=[O:15])=O)=[C:4]([F:20])[CH:3]=1.S(Cl)(Cl)=O.C[N:26](C=O)C>>[Cl:1][C:2]1[C:18]([F:19])=[CH:17][C:5]([C:6]2[NH:8][C:9]3[CH:13]=[CH:12][S:11][C:10]=3[C:14](=[O:15])[N:26]=2)=[C:4]([F:20])[CH:3]=1
Reactant: O=C(Nc1ccsc1C(=O)O)c1cc(F)c(Cl)cc1F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2ccsc12
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
After a mixture of 3-[(4-chloro-2,5-difluorobenzoyl)amino]thiophene-2-carboxylic acid, thionyl chloride and DMF was stirred for 1.5 hours at 75° C., the solvent was removed under reduced pressure and 1,4-dioxane was added. After the reaction solution was added to 28% ammonia water under ice cooling and stirred at room temperature for 3 hours, the solvent was removed under reduced pressure. MeOH and 1M NaOH aq were added to the obtained residue and stirred for 2.5 hours at 90° C. to give 2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4(1H)-one.
Reaction SMILES: [CH3:1][C:2]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)=[O:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[C:4]12([C:2](=[O:3])[CH:1]=[CH:16][N:17]([CH3:19])[CH3:18])[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 37 %

Procedure:
A solution of 17.83 g (0.10 mol) of 1-adamantyl methyl ketone in 35.75 g (0.30 mol) of dimethylformamide dimethylacetal was heated at reflux for 24 hours. After cooling and removal of the solvent in vacuo at 45° to 50° C., the residue was purified by silical gel chromatography to yield 8.64 g (37%) of a white solid: Rf 0.20 in 50% EtOAc/Ligroin; 1H NMR (CDCl3) δ 1.68 (S, 6H, the δ hydrogens of the adamantyl ring, methylene protons at the farthest position from the substituent), 1.81 (S, 6H, the β hydrogens of the adamantyl ring, methylene protons at the closest position to the substituent), 2.00 (S, 3H, the three bridgehead protons, 2.90 (br S, 6H, N(CH3)2), 5.20 (d, 1H, J=14 Hz, O=C-CH), 7.60 (d 1H, J=14 Hz, =C-N<). All analytical data confirmed the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1cc(O)cc(Br)c1
Temperature: -78 °C
Yield: 16 %

Procedure:
1-bromo-3,5-dimethoxybenzene (3.0 g, 13.8 mmol) was dissolved in dichloromethane (45 mL) and the solution was cooled to −78° C. Boron tribromide (1M in dichloromethane, 41 mL, 41 mmol) was added and the solution was warmed gradually to room temperature over 18 hours. After cooling to −78° C., the reaction was quenched with water (100 mL). The organics were separated and washed with sodium thiosulphate solution then water, then dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate 100:0 to 80:20, to afford the title compound in 16% yield (470 mg).
Reaction SMILES: Cl.[C:2]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([NH2:20])[C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:21][N:22]1[CH2:27][CH2:26]N[CH2:24][CH2:23]1>>[C:2]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:20]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[C:8]=2[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Product: CN1CCN(C2=Nc3ccccc3Nc3sc(C(C)(C)C)cc32)CC1
Yield: 78.2 %

Procedure:
By a method similar to Example 59, using 2-tert-butyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.00 g, 3.26 mmol) and N-methyl-piperazine (1.9 g, 19 mmol) to obtain the title compound (904 mg, 78%) as a yellow powder: mp 125–130° C. (dec): 1H NMR (CDCl3) δ 1.29 (s, 9H), 2.35 (s, 3H), 2.50 (m, 4H), 3.53 (m, 4H), 4.96 (s, 1H), 6.33 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.96 (t, 1H), 7.02 (d, 1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:22])[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH3:14])[CH3:10].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.[NH4+].[Cl-]>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:9]([O:11][C:12](=[O:22])[C:13]([CH3:14])([C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH2:27][CH2:26][CH2:25][CH2:24][Br:23])[CH3:10]
Reactant: BrCCCCBr
Reactant: CCOC(=O)C(C)c1ccc(C)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(CCCCBr)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Under N2 atmosphere, LDA (54.5 mL, 110 mmol) was added drop-wise to a stirred solution of 2-p-tolyl-propionic acid ethyl ester (21 g, 110 mmol) in anhydrous THF (190 mL) at −78° C. After 1 h, the reaction mixture was added to a solution of 1,4-dibromo-butane (38 g, 176 mmol) in THF (50 mL) at −78° C., followed by addition of DMPU (20 mL). The reaction mixture was stirred for 2 h, then warmed to rt overnight. The resulting mixture was poured into saturated NH4Cl solution (1000 mL), and extracted with ethyl acetate (4×250 mL). The combined organic layers were washed with brine (300 mL), 1 M HCl (200 mL), saturated NaHCO3 solution (300 mL), and brine (200 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was distilled in high vacuo (bp. 128-130° C./0.2 mmHg) to furnish 6-bromo-2-methyl-2-p-tolyl-hexanoic acid ethyl ester (22 g, 89.5%) as an oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm) 7.19 (d, 2H, J=8.2 Hz), 7.12 (d, 2H, J=8.2 Hz), 4.13 (q, 2H, J=7.2 Hz), 3.37 (t, J=6.6 Hz, 2H), 2.32 (s, 3H), 2.10-1.80 (m, 4H), 1.54 (s, 3H), 1.36 (m, 2H), 1.19 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 176.26, 140.92, 136.35, 129.21, 125.89, 60.88, 49.82, 38.53, 33.61, 33.33, 23.59, 22.78, 21.07, 14.24. HRMS (LSIMS, nba): Calc. for (C16H23BrO2) 327.0959, found 327.0975.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([S:16][CH3:15])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-piperidone (5.00 g) and 4-(methylthio)aniline (3.33 g) was treated in the same manner as described in Preparation Example 37 to give white powder of the title compound.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=1[CH3:42]>CN(C)C=O>[CH3:42][C:33]1[C:34]([C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:13]1[C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=2[N:11]=[C:12]1[C:14]([F:17])([F:15])[F:16]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.12 %

Procedure:
A suspension of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 15 min. 1-(Bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (1.729 g, 6.83 mmol) was added in and the resulting reaction mixture was stirred for 3 h at 80° C. The mixture was then cooled to room temperature and poured into ice/water. The precipitate was collected by filtration, washed with water, then hexanes (turned into a gum on the filter paper-some material was lost). The crude material was purified on a silica gel column (ISCO, eluting with 0-5% MeOH in DCM) to give the desired product (580 mg, 1.099 mmol, 24.12% yield) (several mixed fractions obtained were discarded). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (d, J=2.53 Hz, 1H), 7.61 (d, J=7.83 Hz, 1H), 7.37 (d, J=2.27 Hz, 1H), 7.23 (t, J=7.96 Hz, 1H), 6.29 (d, J=7.58 Hz, 1H), 5.76 (s, 2H), 3.93 (s, 3H), 3.70-3.78 (m, 4H), 3.12-3.22 (m, 4H), 2.53 (s, 3H). MS(ES+) m/e 502 [M+H]+.