Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C(O)(=O)C.CS(C)=O.[BrH:19]>O>[Br:19][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)c1ccccc1O
Reactant: Br
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1cc(Br)ccc1O
Reaction time: 0.5 h

Procedure:
To a mixture of 2-isopropylphenol (3.0 g), acetic acid (30 mL) and dimethylsulfoxide (15 mL) was added dropwise 48% hydrobromic acid (15 mL) at room temperature. The mixture was stirred for 30 min, and poured into water. The resulting mixture was extracted with ethyl acetate. The organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (4.62 g)
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1>>[OH:18][C:16]1[CH:17]=[C:2]2[C:3]([C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:34][N:33]2[C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(-n2nc(-c3ccc(O)cc3O)c3ccc(O)cc32)cc1
Yield: 7.5 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.087 g, 0.5 mmol) to give 0.013 g of product as a tan solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7](OC)=O.[AlH4-].[Li+].S(Cl)(Cl)=O.[C-:20]#[N:21].[Na+]>CCOCC.O.CS(C)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH2:7][C:20]#[N:21])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)ccc1OC
Reactant: [C-]#N
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: O
Product: COc1ccc(Cl)cc1CC#N
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of methyl 5-chloro-2-methoxybenzoate (25.4 g, 127 mmol) in ether (200 ml), cooled in an ice water bath, was added dropwise lithium tetrahydroaluminate (1 M in diethyl ether, 110 ml, 110 mmol). After 2 hours the reaction was quenched with water and then acidified to pH 3 with hydrochloric acid (6 M aqueous solution). The layers were separated and the organic layer dried over magnesium sulfate, filtered and concentrated in vacuo to give a white solid. The solid was dissolved dichloromethane (200 ml) and treated with thionyl chloride (25 ml, 340 mmol). After heating at reflux for 2 hours, the reaction was cooled to room temperature and water added. The layers were separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange solid. This solid was dissolved dimethyl sulphoxide (175 ml), sodium cyanide (12.75 g, 260.2 mmol) added and solution heated to 80° C. for 3 hours. After cooling to room temperature, water was added and a solid formed that was filtered and washed with water to provide the title compound as an off white solid, 20.8 g, 91% yield.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>C1COCC1>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)=[C:14]=[O:15]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C=Nc1ccc(OC(F)(F)F)cc1
Yield: 164.1 %

Procedure:
To a solution of 0.41 ml (3.00 mmol) of 4-(trifluoromethoxy)aniline in 5.4 ml of THF was added 0.22 ml (1.80 mmol) of trichloromethyl chloroformate an heated to reflux for 45 min. The solution was evaporated under reduced pressure, dissolved in toluene and evaporated (2×) to give 0.60 g (99%) of the titled compound as pink solid. MS: 203 M+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][CH:34]=[CH:33][C:16]=1[CH2:17][O:18]/[N:19]=[C:20](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)\[CH2:21][CH2:22][C:23]([O:25]C)=[O:24].CO.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][CH:34]=[CH:33][C:16]=1[CH2:17][O:18]/[N:19]=[C:20](/[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)\[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC/C(=N\OCc1ccccc1OCc1nc(-c2ccccc2)oc1C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO/N=C(\CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of methyl E4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (1.60 g), methanol (5 ml), tetrahydrofuran (10 ml) and 1N aqueous sodium hydroxide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was poured into water, acidified with 2N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated to give E-4-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (1.42 g, yield 91%) as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles. m.p. 116-117° C.
Reaction SMILES: O1CCCC1.C(N(CC)CC)C.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][S:20][C:18]=2[N:19]=1.[CH:30]12[NH:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH:32]([OH:38])[CH2:31]2>O.C(OCC)(=O)C>[Cl:13][C:14]1[N:15]=[C:16]([N:37]2[CH:30]3[CH2:36][CH2:35][CH:34]2[CH2:33][CH:32]([OH:38])[CH2:31]3)[C:17]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][S:20][C:18]=2[N:19]=1
Reactant: OC1CC2CCC(C1)N2
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)csc2n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC1CC2CCC(C1)N2c1nc(Cl)nc2scc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Tetrahydrofuran (2 mL) and triethylamine (0.10 mL, 0.71 mmol) were added to 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine (100 mg, 0.356 mmol) and 8-azabicyclo[3.2.1]octan-3-ol (68 mg, 0.53 mmol). The mixture was stirred overnight at room temperature. Ethyl acetate (2 mL) and water (2 mL) were added and the layers were separated. The aqueous was extracted with ethyl acetate (2×2 mL). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give a brown solid (127 mg). This was purified by silica chromatography (10 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 30%; all output collected). One set of fractions was identified and the relevant fractions were combined and evaporated to give a brown solid (83 mg). This was purified again by LCUV (acidic method 1) to give the target compound as a white solid (44 mg). m/z [M+H]+372.0/373.9. Retention time 4.74 min (LCMS method+ve 6 min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N+:10]([O-])=O)=[O:4]>CO.[Pd]>[NH2:10][C:9]1[CH:8]=[C:7]([C:13]([CH3:16])([CH3:14])[CH3:15])[NH:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1[nH]c(C(C)(C)C)cc1N
Reaction time: 1 h

Procedure:
A Parr hydrogenation bottle fitted with a 16×100 mm disposable glass culture tube is charged with methyl-5-t-butyl-3-nitropyrrole-2-carboxylate (14 mg, 0.062 mmol) in dry methanol (1 mL) and Pd (10% on carbon, 3 mg). The reaction is successively evacuated and purged with H2 gas three times. The reaction mixture is then shaken under an atmosphere of H2 (35 psi) for 1 h, diluted with dichloromethane and filtered through celite. The filtrate is concentrated in vacuo to give methyl 3-amino-5-t-butylpyrrole-2-carboxylate as a bright yellow oil (100%, crude yield). 1H NMR (CDCl3) d 7.89 (br s, 2H), 5.52 (d, 1H, J=2.8 Hz), 3.82 (s, 3H), 1.26 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:29][CH2:30][CH3:31])[C:26](O)=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.ClCCl.CO>CN(C=O)C>[C:26]([CH:25]([O:29][CH2:30][CH3:31])[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:10][CH:11]=2)=[CH:19][CH:20]=1)(=[O:27])[NH2:39]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
3-{4-[2-(4-tert-Butoxycarbonylamino phenyl}ethoxy]phenyl]-2-ethoxypropanoic acid (1.18 g, 2.75 mmole) and benzotriazol-1-yl-oxytri-pyrrolidinophosphoniumhexafluorophosphate (1.43 g, 2.75 mmole) were dissolved in dry DMF (20 ml). Ammonia gas was bubbled through the mixture for 5 minutes. After stirring at room temperature for 16 hours it was checked using HPLC that all the starting material was consumed. Water was added and extracted three times with ethyl acetate dried with magnesium sulfate and evaporated. The residue was redissolved in dichloromethane and chromatography on silica using a gradient system of dichloromethane:methanol (0-5%) gave 1.04 g (85% yield) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[B:28](OCC(C)C)([O:34]CC(C)C)[O:29]CC(C)C.[Cl-].[NH4+]>CCOCC.O1CCCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([B:28]([OH:34])[OH:29])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: CC(C)COB(OCC(C)C)OCC(C)C
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
A solution of tetrahydrofuran (400 mL) of pyridin-2-yl-carbamic acid tert-butyl ester (16 g) described in Manufacturing Example 1-7-1 and N,N,N′,N′-tetramethylethylene diamine (25 g) was cooled to −70° C., n-butyl lithium (78 mL, 2.64 M heptane solution) was added dropwise for 1 hour, and the mixture was stirred for 10 minutes. This mixture was then warmed to between −10° C. and −6° C., and stirred at that temperature for 2 hours. The solution was then cooled again to −70° C., and triisobutyl borate (58 g) was added dropwise for 1 hour. The mixture was warmed to 0° C., and saturated aqueous ammonium chloride solution was added thereto. To the resulting yellow solids was added ether and then stirred, and the solids were filtered and washed with ether and water. The solids were dried under a reduced pressure to obtain the title compound (14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=1>C(C(C)=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][N:24]=2)=[N:4][CH:3]=1
Reactant: Oc1ccccc1Oc1ncc(Cl)cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2Oc2ncc(Cl)cn2)nc1
Yield: 99.6 %

Procedure:
After heating at reflux a mixture of 1.5 grams (0.0067 mole) 2-(5-chloropyrimidin-2-yloxy)phenol, 1.2 grams potassium carbonate, 1.3 grams 2-chloro-5-nitropyridine and 40 ml of methyl ethyl ketone, the reaction mixture was poured into excess H2 0 and the aqueous mixture extracted with ethyl ether (200 ml). The ether layer was washed with saturated NaHCO3, H2O, brine, dried (MgSO4), filtered, and evaporated to yield 2.3 grams of a yellow-orange oil which was purified by silica gel column chromatography (CH2Cl2 as the eluent). NMR (CDCl3): δ6.90 (d, 1H, pyridine ring proton), 7.35 (s, 4H, ArH), 8.25-8.50 (m, 1H, pyridine ring proton), 8.45 (s, 2H, pyrimidine ring protons), 8.95 (d, 1H, pyridine ring proton).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[Br:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:17][CH2:16][CH2:15][Br:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Oc1ccc(Cn2cccn2)cc1
Reactant: BrCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCOc1ccc(Cn2cccn2)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a mixture of 4-(1-pyrazolyl)methylphenol (5 g), 1,3-dibromopropane (11.59 g) and water (50 ml) was added dropwise an aqueous solution of sodium hydroxide (1.38 g) dissolved in water (10 ml) while stirring under heating at reflux over 30 minutes. The reaction mixture was then heated at reflux under stirring for further 1 hour, and then cooled to room temperature, which was extracted with diethyl ether (300 ml). The organic layer was washed with 5N aqueous sodium hydroxide solution and then water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 3-[4-(1-pyrazolyl)methylphenoxy]propyl bromide (4.76 g) as white crystals. Yield, 56%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.CI.[C:23](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:4]=2[C:5](=[O:8])[N:6]([CH3:23])[N:7]=1
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)n[nH]c(=O)c32)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 83.9 %

Procedure:
A mixture of 4-chloro-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (0.43 g, 1.5 mmol), MeI (0.103 ml, 1.65 mmol), potassium carbonate (0.41 g, 3.0 mmol) and DMF (5 ml) was stirred at room temperature for 19 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 0.38 g (98%) of the title compound as crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][C:25]([OH:28])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: COc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A solution of 15 g of 2-bromoanisole in 50 ml of THF is cooled to −70° C., under nitrogen, a 1.6 M solution of n-butyllithium in THF is added dropwise and the mixture is kept stirring for 1 hour. The mixture is cooled to −70° C. and a solution of 15.2 g of 1-benzylpiperid-4-one in 50 ml of THF is added dropwise. The mixture is kept stirring while allowing the temperature to rise to RT and after 1 hour, the reaction mixture is concentrated under vacuum. The residue is taken up in AcOEt, the organic phase washed with water, with a saturated solution of NaCl, dried over MgSO4 and the solvent evaporated under vacuum. 14 g of the expected product are obtained after crystallization from the AcOEt/ether/heptane mixture.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.CN(C=O)C.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a mixture of 1.5 g of 2-(3-bromophenyl)ethanol, 1.0 g of imidazole and 15 mL of DMF was added 2.8 g of tert-butyl(chloro)diphenylsilane under ice cooling, and the followed by stirring for 1 hour at the same temperature then for a day at room temperature. Diethyl ether and water were added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3), thereby obtaining 3.27 g of [2-(3-bromophenyl)ethoxy](tert-butyl)diphenylsilane.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(=O)(O)[O-].[Na+].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].C(Cl)Cl>[O:11]=[C:9]1[CH2:8][O:7][C:6]2[N:12]=[C:2]([C:27]3[CH:41]=[CH:40][C:30]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[CH:29][CH:28]=3)[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:4][C:5]=2[NH:10]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(cc2-c2ccccc2)NC(=O)CO3)cc1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
In a reaction tube was added 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (0.19 g, 0.623 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (0.25 g, 0.750 mmol) in 1,4-Dioxane (10 ml), followed by a solution of sodium carbonate (0.198 g, 1.868 mmol) in water (2.5 ml) to give a suspension. This was degassed followed by the addition of PdCl2(dppf)-CH2Cl2 adduct (0.051 g, 0.062 mmol). The resulting mixture was heated at 80° C. for 20 h. The reaction mixture was cooled down to room temperature and diluted with saturated sodium bicarbonate solution (30 ml) and extracted with ethyl acetate (20 mlX3). The combined organic phase was washed with water, brine and concentrated to give product (0.21 g) used for next step without further purification. LCMS (Method D): RT=1.25 min, M+H+=433.2.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1.[OH-].[Na+].[CH2:18]([N:20]([CH2:44][CH3:45])[CH2:21][CH2:22][N:23]([CH2:41][CH:42]=O)[C:24](=[O:40])[CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BrH:60]>CN1C(=O)CCC1.CO.ClCCl.C(O)C.O>[BrH:60].[BrH:60].[CH2:44]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][N:23]([CH2:41][CH2:42][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[S:12][C:11](=[O:14])[NH:10][C:9]=2[C:8]([OH:15])=[CH:7][CH:6]=1)[C:24](=[O:40])[CH2:25][CH2:26][O:27][CH2:28][CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[CH3:45]
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Reactant: CCN(CC)CCN(CC=O)C(=O)CCOCCc1cccc2ccccc12
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCN(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C(=O)CCOCCc1cccc2ccccc12
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
A suspension of 7-(2-amino-ethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (53 g) in dry NMP (216 mL) was heated to 60° C. and treated in one portion with a solution of NaOH (8.2 g) in methanol (102 mL). The bright orange suspension was cooled to room temperature and treated dropwise with a solution of N-[2-(diethylamino)ethyl]-3-[2-(1-naphthyl)ethoxy]-N-(2-oxoethyl)propanamide in dichloromethane (475 mL) over 20 minutes. The reaction was left to stir for 25 minutes. Sodium triacetoxyborohydride (91.5 g) was then added in portions over 20 minutes and the mixture stirred for a further 50 minutes. The reaction mixture was poured into water (1.8 L) and the acidic solution (pH5) was washed with tert. butyl methyl ether (TBME) (3×500 mL). The aqueous phase was basified to pH8 by the addition of solid potassium carbonate and extracted with dichloromethane (3×750 mL); the combined organic extracts were dried over magnesium sulphate and concentrated to give a dark oil. This was dissolved in ethanol (200 mL) and 48% aqueous hydrobromic acid (73 mL) was added. The solution was aged for 30 minutes then evaporated to dryness. The residue was triturated with ethanol (560 mL); the resultant solid was collected by filtration and dried in vacuo at 50° C. The sticky solid was suspended in boiling ethanol (100 mL) and filtered while hot. The collected solid was dried in vacuo at 50° C. This material was recrystallised from ethanol/water (3:1, 500 mL). After standing overnight the resultant solid was collected by filtration and washed with ice-cold ethanol (75 mL). Drying in vacuo at 50° C. for 24 hr afforded 57 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21]>C1COCC1>[CH:12]([C:11]1[C:2]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:14][CH3:15])=[CH:6][CH:5]=2)=[O:13]
Reactant: CC(=O)NCCN
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NCCNC(C)=O)c(C=O)cc2c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a stirred solution of 2-chloro-6-methoxyquinoline-3-carbaldehyde (2.00 g, 9.0 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added N-(2-aminoethyl)acetamide (2.76 g, 27.1 mmol) and the reaction mixture was stirred for 1 h at 160° C. under microwave irradiation. After cooling to RT, the volatiles were removed at 40° C. under vacuum and the resulting yellow oil was taken up with CH2Cl2 (100 mL). This organic solution was washed with brine (2×10 mL), dried over MgSO4, filtered, and concentrated under vacuum. The residue was finally purified by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) to give N-(2-(3-formyl-6-methoxyquinolin-2-ylamino)ethyl)acetamide SLA 41168 as an orange solid (601 mg, 23% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][N:23]([CH3:27])[N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 95 %

Procedure:
The title compound was prepared in 95% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), MeI and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 4.49 (3H, s), 5.41 (2H, s), 7.27-7.30 (1H, m), 7.38-7.40 (2H, m), 7.52-7.55 (1H, m), 7.79 (1H, d, J=5.2 Hz), 7.84 (1H, s), 7.96 (1H, s), 8.50 (1H, s), 8.67 (1H, d, J=5.1 Hz). [M+H] Calc'd for C17H14ClN7, 352. Found, 352.