Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH3:15].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH2:3]([N:4]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH3:15])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH:2]([CH3:16])[CH3:1]
Reactant: Cc1ccc(C(F)(F)F)cc1NCC(C)C
Reactant: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(C)Cc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C(F)(F)F)ccc2C)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (2-methylpropyl)[2-methyl-5-(trifluoromethyl)phenyl]amine (50 mg, 0.216 mmol) in pyridine (5 mL) in air, at room temperature, was added ethyl 3-[4-(chlorosulfonyl)phenyl]-2,2-dimethylpropanoate (65.9 mg, 0.216 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, then stood overnight. The solvent was evaporated in vacuo to give the crude material which was then purified by MDAP (Method F) to give the required product, 20 mg. LCMS (M+1) 500, RT 1.53 mins.
Reaction SMILES: C(C1N(CC2C=CC(C(OC)=O)=CC=2Cl)C(C=O)=CN=1)CCC.C(O[C:27](=O)[CH:28]([C:35]([OH:37])=[O:36])[CH2:29][C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)C.[CH2:39]([C:43]1[N:44]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:53][CH:52]=2)[C:45](C=O)=[CH:46][N:47]=1)[CH2:40][CH2:41][CH3:42].[OH-].[K+].[Cl-].[Li+].C(C1N(CC2C=CC=CC=2Cl)C(/C=C(\CC2SC=CC=2)/C(O)=O)=CN=1)CCC>O.C(O)C.CN(C)C=O>[CH2:39]([C:43]1[N:44]([CH2:50][C:51]2[CH:52]=[CH:53][C:54]([C:57]([O:59][CH2:60][CH3:61])=[O:58])=[CH:55][CH:56]=2)[C:45](/[CH:27]=[C:28](\[CH2:29][C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)/[C:35]([OH:37])=[O:36])=[CH:46][N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1
Reactant: CCOC(=O)C(Cc1cccs1)C(=O)O
Agent: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OC)cc1Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccc(C(=O)OCC)cc1

Procedure:
The title compound was prepared following the procedure of Example 42 replacing 2-n-butyl-1-[(4-carbomethoxy-2-chlorophenyl)methyl]imidazole-5-aldehyde with 2-n-butyl-1-[(4-carboethoxyphenyl)methyl]imidazole-5-aldehyde ethyl 2-carboxy-3-(2-thienyl)propionate and potassium hydroxide in water-ethanol at ambient temperature with lithium chloride in dimethylformamide at 80°-125° C.; mp 129°-131° C. (d).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:19][C:20]#[N:21]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:19](/[C:18]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH3:14])[CH:17]=2)\[C:20]#[N:21])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc2ccccc2nc1Cl
Product: COc1ccc(/C(C#N)=C/c2cc3ccccc3nc2Cl)cc1OC
Yield: 84.9 %

Procedure:
2-Chloro-3-quinolinecarboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (185 mg) through Method A (production step 2), to thereby yield the target product (yield: 311 mg, 85%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([F:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CCc2cc(F)ccc2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2cc(F)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-Fluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6, 28.1, 28.3, 29.2, 30.1, 35.9, 36.5, 36.6, 36.7, 53.2, 53.4, 56.0, 59.1, 60.4, 60.7, 67.3, 104.7, 104.8, 112.9, 113.1, 114.8, 114.9, 115.0, 115.1, 130.2, 130.7, 130.8, 130.8, 131.1, 137.3, 137.8, 138.1, 160.1, 162.5, 172.5; MS m/z 456.4 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1([C:15]#[N:16])[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[C:15]([C:10]1([NH:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]1)#[N:16]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(N)CCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1(C#N)CCCC1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a stirred mixture of 20.2 g (0.2 mole) triethylamine and 200 ml chloroform cooled in an ice bath, 14.7 g (0.1 mole) 1-amino-1-cyanocyclopentane hydrochloride (the product of Example 14) were spooned in over ten minutes to give a red solution. To that mixture, 11.5 g (0.1 mole) methanesulfonyl chloride in 25 ml chloroform were added dropwise over 30 minutes. The reaction mixture was stirred 30 minutes. The reaction mixture was washed with 25 ml concentrated hydrochloric acid which had been diluted to 50 ml with ice water. The layers were phase separated. The organic layer was washed twice with 50 ml ice water, dried over magnesium sulfate and stripped to give 13 g of the above-identified amber oily product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH3:21][N:22]([CH3:31])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C(#N)C>[CH3:31][N:22]([CH3:21])[CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: CN(C)CCC1CCCCN1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CC#N
Product: CN(C)CCC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 2 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-(dimethylamino)ethyl]piperidine to give colorless crystals, mp. 155°-157° C. (acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18]I)[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[C:23]([CH2:30][OH:31])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[Zn]>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:21]1[CH:22]=[C:23]([CH2:30][OH:31])[CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(CO)cc1Br
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Zn]
Product: CC(C)(C)OC(=O)C[C@@H](Cc1cc(CO)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C

Procedure:
Following the General Procedure of Description 15 (Part A), the zinc insertion product of (6c) is used in situ to cross couple with commercial (3-bromo-4-nitro-phenyl)methanol (232 mg, 1.0 mmol) in the presence of tris(benzylideneacetone)dipalladium (Pd2(dba)3) (23 mg, 0.025 mmol, 2.5 mol-%) and tris(o-tolyl)phosphine (P(o-tol)3) (30 mg, 0.10 mmol, 10 mol-%) in anhydrous degassed DMF (3 mL). Filtration, aqueous work-up, and purification by silica gel column chromatography furnish the title compound (20a).
Reaction SMILES: CN1CCN(CCCNC2N=CN=C3N(C4C=CC([OH:27])=CC=4)N=CC=23)CC1.[H-].[Na+].[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH2:50][N:49]([C:52]1[N:57]=[C:56]([C:58]([O:60]C(C)(C)C)=[O:59])[C:55]([CH2:65][CH2:66][CH2:67]I)=[CH:54][CH:53]=1)[CH2:48][CH2:47]2)=[O:41]>CN(C=O)C>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[NH:39][C:40]([C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:51]=1[CH2:50][N:49]([C:52]1[N:57]=[C:56]([C:58]([OH:60])=[O:59])[C:55]([CH2:65][CH2:66][CH2:67][OH:27])=[CH:54][CH:53]=1)[CH2:48][CH2:47]2)=[O:41]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Reactant: CN1CCN(CCCNc2ncnc3c2cnn3-c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(CCCO)c(C(=O)O)n1)CC2
Reaction time: 0.17 h

Procedure:
To a solution of compound 84A (60 mg, 0.163 mmol) in DMF (5 ml) was added sodium hydride (32.7 mg, 0.816 mmol)(60%). The reaction was stirred for 10 min and compound 96D (107 mg, 0.163 mmol) was added. The resulting mixture was stirred for 3 hour and purified by reverse phase HPLC (mobile phase: 0%-50% acetonitrile in 0.1% TFA aqueous solution during 70 min) to provide the title compound 99: 1H NMR (400 MHz, DMSO-D6) δ ppm 12.81 (1H, s), 8.04 (1H, dd), 7.79 (1H, d), 7.60 (1H, d), 7.53 (1H, d), 7.45-7.50 (1H, m), 7.39-7.43 (1H, m), 7.32-7.38 (2H, m), 6.95 (1H, d), 4.92 (2H, s), 3.86 (2H, t), 3.37 (2H, t), 2.99 (2H, t), 2.63-2.70 (2H, m), 1.58-1.69 (2H, m), LCMS (APCI) 489 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1C=CC=CC=1>[CH3:15][S:16]([O:1][CH:2]([CH3:7])[CH2:3][CH2:4][C:5]#[N:6])(=[O:18])=[O:17]
Reactant: CC(O)CCC#N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(CCC#N)OS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a cooled (ice bath) stirred solution of 4-hydroxypentanonitrile (18.8 g, 0.19 mol) in benzene (100 ml) and triethyl amine (20 g, 0.198 mol) was added dropwise a solution of methanesulphonyl chloride (22.34 g 0.195 mol) in benzene (20 ml) over a period of 40 min. After addition was complete the stirring was continued for 20 min at room temperature. The solid (TEA.HCl) was filtered off and washed with benzene. The filtrate and washings were combined and concentrated in vacuo to give 37.7 g of the title compond containing approximately 12% of benzene: 1Hmr (CDCl3) δ: 7.38 (3H, benzene), 4.82 (1H, q, J=13 Hz), 3.1 (3H, s), 2.48 (2H, dt), 2.0 (2H, dt) and 1.46 ppm (3H, t, J=13 Hz); ir (neat) νmax : 2243 cm-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N:13]1([C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=3)[N:24]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[F:31][C:28]([F:29])([F:30])[C:25]1[N:23]2[C:22]([CH:21]=[CH:20][C:19]([N:13]3[CH2:18][CH2:17][N:16]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)(=[O:11])=[O:10])[CH2:15][CH2:14]3)=[N:24]2)=[N:27][N:26]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#Cc1ccc(S(=O)(=O)N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 32 %

Procedure:
Obtained in 32% yield by an analogous procedure to Example 394, starting from 4-cyanobenzenesulfonyl chloride and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:19]([O:15][C:13]([CH:12]1[CH2:16][CH2:17][CH2:18][NH:11]1)=[O:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCO
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCOC(=O)C1CCCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 24.9 g. (0.01 mol.) of N-carbobenzoxy-DL-proline and 11.22 g. (0.11 mol.) of n-hexanol in 200 ml. of dry dimethylformamide and 7.9 g. pyridine at room temperature is added 20.6 g. (0.01 mol.) of N,N'-dicyclohexylcarbodiimide. After stirring this mixture at room temperature for 16 hours, the precipitated N,N'-dicyclohexylurea is filtered off, the filtrate is diluted with a large volume of saturated aqueous sodium chloride, and this is thoroughly extracted with chloroform. The combined extracts are dried and concentrated in vacuo to give an oil comprising 1-(benzyloxy)carbonyl)]-2-[(hexyloxy)carbonyl]pyrrolidine.
Reaction SMILES: [O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][Br:20])=[CH:15][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccccc1)c1ccc(CBr)cc1
Yield: 16.3 %

Procedure:
To a CCl4 solution (1 mL) of the product of Step B (126 mg, 0.495 mmol) was added N-bromosuccinimide (44 mg, 246 mmol) and a catalytic amount of AIBN. The solution was refluxed for 30 minutes and then concentrated in vacuo. The residue was purified on a silica gel flash chromatography column (150×30 mm) eluted with 5% ethyl acetate/hexane to afford 27 mg (33%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:3][CH2:2]1.C1(C2C=CC(C(O)=O)=NC=2OCC2CCCO2)CC1.Cl.[NH2:41][C:42]([CH2:50][CH3:51])([CH2:48][CH3:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([NH:41][C:42]([CH2:48][CH3:49])([CH2:50][CH3:51])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:20])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CCOCC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Agent: O=C(O)c1ccc(C2CC2)c(OCC2CCCO2)n1
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CCOCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(tetrahydro-pyran-4-ylmethoxy)-pyridine-2-carboxylic acid (which can e.g. be prepared in a similar manner than 5-cyclopropyl-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 166 b)) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials. MS (EI): m/e=419.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([OH:30])=[C:20]([C:25](OCC)=[O:26])[CH:21]=[N:22]2)=[CH:17][CH:16]=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:20]2[CH:21]=[N:22][C:23]3[C:18]([C:19]=2[OH:30])=[CH:17][CH:16]=[C:15]([F:14])[CH:24]=3)=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(F)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(F)ccc2c1O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 4-chlorobenzylamine (0.52 mL) in 5 mL of toluene is added 2.13 mL of a 2.0 M solution of trimethylaluminum in toluene. The solution is stirred for 5 min at 0° C. and then a suspension of 0.50 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate (J. Med. Chem., 20, 1001 (1977)) in 5 mL of toluene is added. The solution is stirred at 0° C. for an additional 10 min and then it is stirred 18 h at 90° C. The mixture is cooled to 25° C. and it is poured onto a mixture of a large excess of 3 M hydrochloric acid and ice. After stirring the mixture vigorously for 30 min it is filtered. The solid is dissolved in 50 mL of warm glacial acetic acid and distilled water is added to the resulting solution until it is cloudy. The mixture is then allowed to stand for several hours at 5° C. Filtration of this mixture gives the desired amide as 150 mg of a solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH2:19][OH:20])[C:17]#[N:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:20][CH2:19][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=1)[C:17]#[N:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC(CO)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
TBS-Cl (2.29 g, 15.2 mmol) in dry DMF (12 mL) was added to a solution of 2-(4-chlorophenyl)-3-hydroxypropanenitrile (2.30 g, 12.7 mmol) and imidazole (3.45 g, 50.7 mmol) in DMF (20 mL) at 0° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was partitioned between ether and water. The organic layer was washed with brine, dried and concentrated. The residue was purified by column (hexanes:EtOAc, 30:1) to give 3-(tert-butyldimethylsilyloxy)-2-(4-chlorophenyl)propanenitrile (3.40 g, 91%) as a colorless oil. A solution of EtMgBr in THF (3.0 M, 7.0 mL, 21 mmol) was added dropwise at room temperature to a stirred solution of this 3-(tert-butyldimethylsilyloxy)-2-(4-chlorophenyl)propanenitrile (3.1 g, 10 mmol) and Ti(i-PrO)4 (3.4 mL, 11 mmol) in Et2O (60 mL). After the mixture was stirred at room temperature for 1 hour, BF3OEt (2.7 mL, 21 mmol) was added at once. The mixture was stirred for an additional 1 hour. A solution of 10% NaOH (10 mL) was added, followed by DCM (300 mL). The resulting precipitate was filtered and washed with DCM. The combined filtrates were dried and concentrated. The residue was purified by column chromatography (30:1 DCM:MeOH) to give 1-(2-(tert-butyldimethylsilyloxy)-1-(4-chlorophenyl)ethyl)cyclopropanamine (2.3 g, 67%) as a colorless oil. LCMS: 326.1 [M+H+] (APCI+); Rf: 3.04 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)c1c(C)cc(Br)cc1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
A solution of 4-bromo-2,6-dimethyl-benzoic acid (4.04 g, 17.6 mmol) in acetone (50 mL), was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.43 g, 21 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate evaporated under reduced pressure. Silica gel column chromatography using 10% ethyl acetate in hexanes afforded 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.44 g, 80%). GC-MS: m/z 244 M+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]#[N:25])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:27]([O-])=O.[Na+]>O1CCOCC1.O>[OH:19][CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:4]=[C:3]([C:24]#[N:25])[C:2]3[N:1]=[N:27][N:8]([CH3:9])[C:7]=3[CH:6]=2)=[CH:11][C:12]=1[C:20]([F:23])([F:21])[F:22]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCO)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
3-Amino-6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)-picolinonitrile (11 g) was dissolved in dioxane (20 ml), and water (20 ml). 1M HCl (16.39 ml) was added. Sodium nitrite (2.111 g) in water (2 mL) was added and reaction mixture was stirred at room temperature for 2 hrs. Product crashed out and was filtered, washed with water, ether and dried in oven to give 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (5.7 g) as a pale brown solid. 1H NMR (MeOH) δ: 8.55 (s, 1H), 8.43 (m, 2H), 7.36 (d, 1H), 4.45 (s, 3H), 4.25 (t, 2H), 3.95 (t, 2H). MS m/z 364 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>C1COCC1>[CH2:29]([O:14][C@H:13]1[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of benzyl rel-(3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (1 g, 2.97 mmol) in dry THF (10 mL) at 0° C. was added NaH (475 mg, 11.88 mmol). The reaction mixture was stirred at 0° C. for 1 h. Allyl bromide (1.08 g, 8.92 mmol) was added to the reaction mixture dropwise. The reaction mixture was stirred at 0° C. for 2 h and room temperature for 1 h. The reaction was quenched by adding MeOH (5 mL) and was concentrated under reduced pressure to remove most of the solvent. Then water (15 mL) was added to the reaction mixture. EtOAc (15 mL×3) was added to extract the product. The organic phases were combined, dried over MgSO4, filtered, concentrated and subjected to column chromatography (EtOAc:hexanes, 1:3 to 1:1) as the eluent to give benzyl rel-(3R,4R)-3-(allyloxy)-4-[(tert-butoxycarbonyl)amino]pyrrolidine-1-carboxylate (806.2 mg, 72%).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[OH-].[Na+]>O.[Fe].S([O-])([O-])(=O)=O.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([OH:11])=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: [Fe+2]
Agent: [Fe]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Cc1cc(F)c(N)cc1O
Yield: 43.6 %

Procedure:
A mixture of 4-fluoro-2-methyl-5-nitrophenol (2.1 g, 13 mmol), iron powder (1 g, 18 mmol) and iron(II)sulphate (1.5 g, 10 mmol) in water (40 ml) was refluxed for 4 hours. The reaction mixture was allowed to cool, neutralised with 2M aqueous sodium hydroxide and extracted with ethyl acetate (100 ml). The ethyl acetate extract was dried (MgSO4) and the solvent removed by evaporation to give 2-fluoro-5-hydroxy-4-methylaniline (0.8 g, 47%) as a solid.
Reaction SMILES: [OH:1][C:2]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=2)=[CH:31][CH:30]=1)([C:5]1[N:6]=[CH:7][N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)[CH2:3][CH3:4].Cl>[C].[Pd]>[OH:1][C:2]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:36]=2)=[CH:33][CH:34]=1)([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)[CH2:3][CH3:4]
Reactant: CCC(O)(c1ccc(-c2cccc(NC(C)=O)c2)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Product: CCC(O)(c1ccc(-c2cccc(NC(C)=O)c2)cc1)c1c[nH]cn1
Yield: 84.2 %

Procedure:
By the reaction in the same manner as in Example 41-(ii) using N-[4′-[1-hydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl][1,1′-biphenyl]-3-yl]acetamide (1.31 g), 10% palladium carbon (1.31 g) and 1N hydrochloric acid (2.27 ml), the colorless amorphous title compound (640 mg) was obtained.