Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1.CO.N.C(Cl)Cl>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[Cl:14])[N:3]=1
Reactant: NCCCNCc1ccc(Cl)c(Cl)c1
Reactant: COc1cc(Cl)nc2cccc(Cl)c12
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NCCCNCc2ccc(Cl)c(Cl)c2)nc2cccc(Cl)c12
Temperature: 100 °C

Procedure:
A mixture of 2,5-dichloro-4-methoxyquinoline (0.12 g, 0.53 mmol) and N-(3-aminoprop-1-yl)-3,4-dichlorobenzylamine (0.37 g) was heated at 100° C. for 8 h. The resulting mixture was submitted to column chromatography (silica gel, MeOH:NH3:CH2Cl2 10:1:150→10:1:100) to give the title compound as a colourless film, (93 mg, 41%). δH (CDCl3) 1.70-1.87 (m, 3H+H2O), 2.74 (t, J=6.3, 2H), 3.54-3.65 (m, 2H), 3.72 (s, 2H), 3.91 (s, 3H), 5.22 (br, t, 1H), 5.90 (s, 1H), 7.10-7.17 (m, 2H), 7.28-7.37 (m, 2H), 7.40-7.45 (m, 2H); MS (ES+) 424 (MH+, 37%), 249 (100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([OH:32])=[O:31].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:37]1[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=1)[C:30]([OH:32])=[O:31])=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cccc(Oc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To [4-(3-hydroxy-phenyl)-8-trifluoromethylquinolin-3-yl]-phenyl methanone (0.1 g, 0.00025 mole) and 3-carboxyphenyl boronic acid (0.12 g, 0.00072 mole) in 2 ml dichloromethane was added copper acetate (0.091 g, 0.0005 mole) and triethylamine (0.1 ml, 0.00072 mole). This mixture was stirred at room temperature overnight. The reaction was then filtered and the filtrate evaporated to dryness. The crude product was purified by flash chromatography to give 0.027 g of 3-[3-(3-benzoyl-8-trifluoromethyl-quinolin-4-yl)-phenoxy]-benzoic acid: MS: MS (ESI) m/z 514; MS (ESI) m/z 512.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccccc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1cc(Br)ccc1F
Temperature: 2 °C

Procedure:
To a solution of 5′-amino-2′-fluorobiphenyl-2-carbonitrile (11.17 g, 52.6 mmol) in 1,4-dioxane (60 ml) was added 48% hydrobromic acid (250 ml) and the resulting suspension was cooled to 2° C., whilst stirring with an air stirrer. To this was added, dropwise over 20 min, a solution of sodium nitrite (4.18 g, 60.6 mmol) in water (11 ml), keeping the temperature below 5° C. The mixture was then stirred at 2±2° C. for 2 h before adding a cooled (5° C.) solution of freshly purified copper(I) bromide (25.40 g, 177.1 mmol) in 48% hydrobromic acid (75 ml). The mixture was stirred at 1±1° C. for 10 min before heating to 47° C. over 1 h. The mixture was diluted with ice-cold water (1.25 l) and extracted with ethyl acetate (2×500 ml). The combined organic extracts were washed with 1 M aqueous Na2SO3 (100 ml), then saturated aqueous NaCl (100 ml), dried (MgSO4) and evaporated in vacuo to leave 16.08 g of 5′-bromo-2′-fluorobiphenyl-2-carbonitrile as a light brown solid: 1H NMR (360 MHz, CDCl3) δ 7.12 (1H, t, J 9.1 Hz), 7.47-7.57 (4H, m), 7.68 (1H, td, J 7.7, 1.3 Hz), 7.79 (1H, d, J 7.8 Hz).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[NH2:6][CH2:7][C@@H:8]([CH3:29])[O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2>>[OH:3][CH2:2][C:1]([NH:6][CH2:7][C@H:8]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[C:12]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)=[N:13][CH:14]=[N:15]2)[CH3:29])=[O:5]
Reactant: O=C(O)CO
Reactant: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CN)c23)ccc1O
Product: Cc1cc(Nc2ncnc3cccc(O[C@H](C)CNC(=O)CO)c23)ccc1O
Yield: 59 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 4-({5-[(1R)-2-amino-1-methylethoxy]quinazolin-4-yl}amino)-2-methylphenol to give 2-hydroxy-N-[(2R)-2-({4-[(4-hydroxy-3-methylphenyl)amino]quinazolin-5-yl}oxy)propyl]acetamide as a dark brown solid in 59% yield; NMR spectrum (DMSO-d6) 1.41 (d, 3H), 2.17 (s, 3H), 3.43 (dt, 1H), 3.75 (dt, 1H), 3.78 (s, 2H), 5.01 (m, 1H), 6.84 (d, 1H), 7.30 (d, 1H), 7.32 (dd, 1H), 7.39 (d, 1H), 7.46 (d, 1H), 7.95 (t, 1H), 8.22 (t, 1H), 8.75 (s, 1H), 9.54 (d, 1H), 10.78 (s, 1H); Mass spectrum MH+ 383.
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH2:1]([CH2:8][NH:9][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: NCCc1ccccc1
Product: c1ccc(CCNC2CCOCC2)cc1

Procedure:
The title compound was prepared according to Preparation 85 from N-benzylmethylamine and tetrahydro-4H-pyran-4-one. Purification of the crude material by chromatography using dichloromethane/methanol (98:2) as the eluent gave the title compound as a yellow oil. δH (CD3OD): 7.50-7.40 (5H, m), 4.08 (2H, m), 4.06-(2H, s), 3.49-3.40 (2H, ddd), 3.23-3.14 (1H, m), 2.51 (3H, s), 2.03-1.97 (2H, m), 1.89-1.76 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][CH:6]=[CH:5][N:4]=2.[CH:33]1([CH2:36][NH2:37])[CH2:35][CH2:34]1>C1COCC1>[CH:33]1([CH2:36][NH:37][C:11]([C:10]2[CH:9]=[C:8]3[C:3](=[C:2]([Cl:1])[C:15]=2[NH:14][C:13]([C:16]2[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:23])([F:24])[F:22])[CH:20]=2)=[O:12])[N:4]=[CH:5][CH:6]=[N:7]3)=[O:32])[CH2:35][CH2:34]1
Reactant: NCC1CC1
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nccnc3cc12
Solvent: C1CCOC1
Product: O=C(NCC1CC1)c1cc2nccnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reaction time: 8 h
Yield: 74 %

Procedure:
0.55 g (1.15 mol) 9-chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5,8-triaza-anthracen-4-one and 0.5 ml C-cyclopropylmethylamine is dissolved in 15 ml THF and stirred for 8 hours. After evaporation, the residue is crystallised in diethyl ether to give 0.47 g (74%) of the title compound. m.p.: 180-183° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([C:15]3[CH:19]=[CH:18][O:17][C:16]=3[CH3:20])[CH:12]=[CH:11][N:10]=2)[CH2:3]1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:21][C:12]1[C:13]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH3:20])=[N:14][C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[N:10][CH:11]=1
Reactant: Cc1occc1-c1ccnc(N2CC(C)OC(C)C2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
2,6-Dimethyl-4-[4-(2-methyl-3-furanyl)-2-pyrimidinyl]morpholine (737 mg, 2.70 mmol) was dissolved in chloroform (13 mL), cooled in an ice bath and treated with N-bromosuccinimide (480 mg, 2.70 mmol). The resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound (719 mg, 2.041 mmol, 76% yield) as a white solid. LC/MS [M+H]+=352/354.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=1.[BH4-].[Na+].O>CO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1
Reactant: O=Cc1cnc(C2OCCO2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cnc(C2OCCO2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole-5-carbaldehyde (7.00 g) in methanol (30 mL) was slowly added sodium borohydride (0.53 g) at 0° C., and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.59 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 188 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(O)(=O)C.[Cl:15][CH2:16][C:17](Cl)=[O:18].O.O.O.C([O-])(=O)C.[Na+]>O>[Cl:15][CH2:16][C:17]([NH:4][C:3]1[C:5]([CH3:10])=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C)c(N)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(C)c(NC(=O)CCl)c1C
Reaction time: 0.5 h

Procedure:
A mixture of 7.8 g of 2,3,6-trimethylaniline R. A. Scherrer and H. R. Beatty, J. Org. Chem. 37, 1681 (1972), and 50 ml glacial acetic acid was cooled to 10° C. in a glass stoppered bottle, 7.23 g chloroacetyl chloride was added, mixed quickly and followed immediately by a cooled solution of 19.3 g sodium acetate trihydrate in 80 ml water. The mixture was shaked for 30 min. and the solid material was filtered off and washed carefully with water. After drying, a yield of 9.94 g (81%) was obtained. It melted at 145°-146° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])=[CH:7]2.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:11][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CC1=Cc2cccc(Cl)c2C1
Solvent: CCOCC
Product: CC1=Cc2cccc(-c3ccccc3)c2C1
Temperature: 1 °C

Procedure:
A 5 L round bottom flask was equipped with mechanical stirring, a reflux condenser and ice bath. 488.2 g distilled 7-chloro-2-methylindene (2.97 mol) was added, dissolved in 2 L ether and 32.2 g Ni(dpp) (0.059 mol, 2 mol%) slurried in the solution, and stirred to cool to 0-2° C. 1.05 L of 3.1M phenylmagnesium bromide in ether (3.25 mol, 10% excess) was added slowly from an addition funnel so that the temperature remained below 5° C. Once complete, the ice bath was removed, and the reaction stirred up to room temperature. The reaction was refluxed for 8 hours, and checked for completion by GC. The reaction flask was cooled with an ice bath, and 250 mL water added, then 1 L 10% HCl. The aqueous and organic layers are separated, and the organic layer dried over anhydrous Na2SO4. Ether was distilled, and the residual oil placed on a column of 100 g silica gel. Elution with hexane was performed, the hexane distilled under reduced pressure to a temperature of 90° C. 2-methyl-7-phenylindene (Spaleck compound 13a) was obtained by distillation at <1 mm Hg with a 36 cm Vigreux column at 125° C. A fore-cut containing biphenyl was obtained at 70-90° C. and discarded. Yield was 507.8 g (2.47 mol) equal to 80%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[N:9]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([F:13])[CH:15]=1)[CH:8]=[CH:7]2
Reactant: COc1ccc(Cl)c2[nH]ccc12
Reactant: COc1ccc(B(O)O)cc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2ccc3c(OC)ccc(Cl)c32)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.7 %

Procedure:
To a solution of 7-chloro-4-(methyloxy)-1H-indole (D11) (1.15 g, 6.35 mmol) in dichloromethane (20 mL) was added 3-fluoro-4-methoxyphenylboronic acid (2.2 g, 12.9 mmol), triethylamine (1.8 mL, 12.9 mmol), copper (II) acetate (2.3 g, 12.7 mmol) and powdered 4A molecular sieves (2.0 g). The reaction mixture was stirred at room temperature in the presence of air for 3 days. Further quantities of 3-fluoro-4-methoxyphenylboronic acid (440 mg), triethylamine (0.36 mL) and copper acetate (440 mg) were added and the mixture stirred at room temperature in the presence of air for a further 16 hours. The mixture was filtered and the solid washed with dichloromethane. The filtrate was concentrated at reduced pressure. The product was partially purified by silica gel chromatography eluting with 2-35% dichloromethane in hexane. The resulting product was partially dissolved in dimethylsulphoxide and acetonitrile. The undissolved solid was collected by filtration to yield the title compound (D12) (440 mg). The filtrate was concentrated at reduced pressure and the product purified by MDAP to yield a further batch of the title compound (D12), (143 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:39](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31]([C:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:7]([C:11]([OH:13])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc(Cl)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dichloromethane (4.5 L) solution of 2-butyl-4-chloro-1-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylic acid (235 g, 0.54 mol) was added triethylamine (85 mL, 0.59 mol), followed by a dichloromethane (800 mL) solution of trityl chloride (159 g, 0.56 mol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Chromatography over silica eluting with 20-80% acetone/heptane afforded the title compound as an orange solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[C:11]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](O)CC1)OCc1ccccc1

Procedure:
Commercially available trans-4-aminocyclohexanol hydrochloride (50 g, 0.33 mol) was treated with benzyl chloroformate (Cbz-Cl) (51.8 mL, 0.36 mol) under standard Schotten-Baumann conditions to provide N-Cbz-trans-4-aminocyclohexanol (62.33 g, 88% yield) as a white solid: m.p. 160°-162° C.; 1H NMR (300 MHz) δ 7.36 (m, 5H), 5.10 (s, 2H), 4.58 (br, 1H), 3.61 (m, 1H), 3.51 (m, 1H), 2.01 (br t, 4H, J=13.5 Hz), 1.40 (m, 2H), 1.20 (m, 2H); MS: (M+H)+ =250, (M+H+NH3)+ =267.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>N1C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:22](=[O:23])[O:24][CH2:25][CH3:26])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccc(N(Cc2ccc(Cl)cc2)C(=O)OCC)cc1
Temperature: 100 °C

Procedure:
A stirred solution of ethyl 4-(4-chlorobenzylamino)-benzoate (5.8 g; 0.02 mole) in pyridine (50 ml) was treated dropwise with ethyl chloroformate (2.5 g; 0.023 mole) at room temperature. The mixture was heated to 100° C. for 30 minutes, cooled and added to iced water (100 ml). After neutralisation with dilute hydrochloric acid the product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and the solvent evaporated. The residual oil was purified by chromatography on silica-gel in dichloromethane to give ethyl N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-carbamate as a colourless oil (4.86 g; 56%) which solidifed on standing. M.p. 43°-6° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[C:11]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C(=O)O)cn1
Temperature: 140 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
A mixture of 6-aminonicotinic acid 5.00 g (36.5 mmol) and acetic anhydride 3.80mL (40.2 mmol) in pyridine 30 mL was stirred at 140° C. for 24 hours. To the reaction mixture was added ethyl acetate and acidified with diluted HCl solution to pH 2. The organic layer was washed with water and brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed with diisopropyl ether to give the title compound 1.70 g as off-white solid. Yield 26%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][C:13](=[O:16])[CH:14]=[CH2:15].[OH-].[Na+]>CCOC(C)=O.O.[Fe]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=1
Reactant: C=CC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)Nc1cc(N)ccc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of N-(2-methoxy-5-nitro-phenyl)-acrylamide (Step 1) (335 mg, 1.51 mmol), iron powder (0.51 g, 9.0 mmol), FeSO4 (839 mg, 3.02 mmol), Celite® (0.3 g) and water (9 mL) was heated to reflux with stirring for 3 h. The reaction mixture was cooled to RT. The solution was made basic to pH 13-14 by the addition of 2 N NaOH. The reaction mixture was diluted with EtOAc and water. The solution was filtered to remove the solids and solids were washed with EtOAc. The aqueous layer was extracted three times with EtOAc (100 mL) and the combined organics were dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography using EtOAc as the solvent to give N-(5-amino-2-methoxyphenyl)-acrylamide.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:9]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(#N)C.[CH:53]([C@H:55]1[CH2:60][CH2:59][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:57][CH2:56]1)=O>C1COCC1>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:21]1[N:22]=[N:23][N:24]([CH3:26])[N:25]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:53][C@H:55]2[CH2:56][CH2:57][C@H:58]([C:61]([O:63][CH3:64])=[O:62])[CH2:59][CH2:60]2)[C:10]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:9]1=2
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: Cc1cc(C)c2c(c1)[C@@H](N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)cc(C)c32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Charge a flask equipped with an overhead stirrer, temperature probe, nitrogen inlet with (S)—N-(3,5-bis(trifluoromethyl)benzyl)-7,9-dimethyl-N-(2-methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-amine (5 g, 10.03 mmoles) and sodium triacetoxyborohydride (3.19 g, 15.05 mmoles) and acetonitrile (40 mL) Immerse the flask in an ice bath to cool the slurry to below about 5° C., then add (trans)-methyl 4-formylcyclohexanecarboxylate (2.99 g, 17.57 mmoles, prepared essentially according to the procedures in Houpis, I. N. et al, Tetrahedron Let. 1993, 34(16), 2593-2596 and JP490-48639) dissolved in THF (10 mL) via a syringe while maintaining the reaction mixture at or below about 5° C. Allow the reaction to warm to RT and stir overnight. Add NH4Cl (25 mL, 50% saturated aqueous solution) and separate the aqueous layer from the organic layer. The pH of the organic layer should be about 5.5. Warm the organic layer to about 45° C. and add water (16 mL). Add a seed crystal of the titled compound and cool to about 35° C. Collect the resulting solid by filtration and rinse with ACN. Dry to provide 5.80 g of the title compound.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]2.[Br:20][C:21]1[N:22]=[C:23]([C:42]#[CH:43])[C:24]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:25][CH:26]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.FC(F)(F)C(O)=O>CO>[C:38]([O:37][C:35]([N:27]([C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:24]1[C:23]([C:42]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]4)[CH:43]=2)=[N:22][C:21]([Br:20])=[CH:26][N:25]=1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C=NO)ccc21
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)no1
Reaction time: 17 h
Yield: 16.5 %

Procedure:
A solution of tert-butyl 5-((hydroxyimino)methyl)-1H-indole-1-carboxylate (260.3 mg, 1 mmol) in methanol (1 mL) was added slowly to a stirred solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (438.1 mg, 1.100 mmol) and (diacetoxyiodo)benzene (354.3 mg, 1.100 mmol) in methanol (2 mL) containing trifluoroacetic acid (15 μL, 0.1947 mmol) at ambient temperature. The reaction was stirred at this temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column) loaded with dichloromethane and eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrate in vacuo to give the sub-title product as a white solid (108 mg, 16% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.22 (s, 18H), 1.57 (s, 9H), 6.73 (d, 1H), 7.69 (d, 1H), 7.80 (s, 1H), 7.89 (dd, 1H), 8.11 (d, 1H), 8.23 (d, 1H) and 8.94 (s, 1H) ppm.