Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[NH:19]([C:23]1[S:24][CH:25]=[C:26]([CH2:28][S:29][CH2:30][CH2:31][NH2:32])[N:27]=1)[C:20]([NH2:22])=[NH:21]>CN(C)C=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C:6]1[C:7](=[O:9])[NH:8][C:3]([NH:32][CH2:31][CH2:30][S:29][CH2:28][C:26]2[N:27]=[C:23]([NH:19][C:20]([NH2:22])=[NH:21])[S:24][CH:25]=2)=[N:4][N:5]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Solvent: CN(C)C=O
Product: COc1cccc(Cc2nnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)c1
Temperature: 135 °C
Reaction time: 192 h
Yield: 5.9 %

Procedure:
A mixture of 3-methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.0 g) and 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (0.924 g) was heated at 135° C. for 3 hours. The residue was dissolved in dimethyl formamide (20 ml) and the solution was allowed to stand at room temperature for 8 days. A yellow brown solid precipitated out of solution, and this was filtered off and dried in air, then purified using pressure assisted short bed column chromatography (Kieselgel 60) with chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.3 v/v/v as eluant, to give 6-(3-methoxybenzyl)-3-[2-(2-guanidinothiazol-4-yl-methylthio)ethylamino]-1,2,4-triazin-5-one (0.1 g). The n.m.r. spectrum of the product in d4 acetic acid using tetramethylsilane as an internal standard (δ=0) had the following resonances (δ): 2.8 (2H, multiplet); 3.5 (2H, multiplet); 3.75 (5H, singlet); 3.9 (2H, singlet); 6.8-6.9 (4H, multiplet); 7.2 (1H, broad doublet).
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.Cl.[F:24][C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: Nc1cccc(F)c1
Agent: Cl
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3-fluorophenyl)amine hydrochloride instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.04 (s, 3H), 2.20 (s, 3H), 4.51 (d, J=5.6 Hz, 2H), 6.67 (t, J=5.9 Hz, 1H), 7.05-7.29 (m, 4H), 7.60 (bs, 1H), 7.69 (t, J=8.1 Hz, 1H), 8.08 (s, 1H), 8.48 (d, J=4.0 Hz, 1H); MS (ESI) m/z 324.4 (M+1)+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[CH:59]=[CH:58][C:10]([CH2:11][C:12]2[CH:13]=[C:14]([C@H:19]3[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:20]3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:9][CH:8]=1)C=C.C([O-])(=O)C.[Na+]>C(O)(=O)C.[Pd](Cl)Cl>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([C@H:19]2[C@H:24]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[O:20]2)=[CH:13][C:12]=1[CH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][OH:4])=[CH:59][CH:58]=1
Reactant: C=CCOCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: OCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 70 °C
Yield: 42 %

Procedure:
(2S,3S,4R,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (intermediate BK) (50 mg, 0.061 mmol) was taken up in 90% aqueous acetic acid (1 mL), and sodium acetate (30.4 mg, 0.37 mmol) was added, followed by palladium (II) chloride (27.4 mg, 0.154 mmol). The mixture was heated at 70° C. for 5 h. Solvent was evaporated and the residue was taken up in 2 mL DCM and the mixture was filtered through a short Celite® pad. The pad was washed with a copious amount of DCM until all material had eluted. After evaporation of solvent, the residue was purified by TLC using 4:1 hexane:EtOAc to obtain intermediate BL (20 mg, yield 42%). LC-ESI-MS (m/z): 770 (M+H), 791 (M+H+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:26][CH2:27][CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.COC1C=C2C(C(OCC3N4C=C(C5CCNCC=5)C=CC4=NN=3)=CC=N2)=CC=1>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:26][CH2:27][CH2:28][NH:29][CH3:30])=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)NCCN(C)C(=O)OC(C)(C)C)cn34)ccnc2c1
Agent: COc1ccc2c(OCc3nnc4ccc(C5=CCNCC5)cn34)ccnc2c1
Product: CNCCNC(=O)c1ccc2nnc(COc3ccnc4cc(OC)ccc34)n2c1

Procedure:
tert-Butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate was deprotected as previously described for 7-methoxy-4-((6-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methoxy)quinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11](OC)=[O:12])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=2)=[N:4][CH:3]=1
Reactant: COC(=O)c1cccc(-c2ncc(C)cn2)c1
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2cccc(CO)c2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.65 g (7.16 mmol) of methyl 3-(5-methylpyrimidin-2-yl)benzoate, dissolved in 7 ml of THF, are added dropwise under a nitrogen atmosphere to a suspension of 272 mg (7.16 mmol) of lithium aluminium hydride in 7 ml of THF, and the mixture is stirred at room temperature for 24 h. 4 ml of a THF/water mixture (1:1) are subsequently added dropwise. A solution of 1.5 g of Na2CO3 in 4 ml of water is then added, the precipitate is filtered off with suction, and the residue is boiled with 2×THF/ethyl acetate and again filtered off with suction. The combined mother liquors are evaporated to dryness, the residue is dissolved in dichloromethane, and the solution is dried over sodium sulfate, filtered and again evaporated to dryness. The crude product is purified by column chromatography on silica gel; product: 500 mg; ESI: 201 (M+H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](=[N:5][OH:6])[NH2:4].[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>>[NH2:4][C:3](=[N:5][O:6][CH:11]=[CH:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])[C:2]([F:8])([F:7])[F:1]
Reactant: NC(=NO)C(F)(F)F
Reactant: C#CC(=O)OCC
Product: CCOC(=O)C=CON=C(N)C(F)(F)F

Procedure:
The title compound was prepared using the procedure described in Example 65(b) starting from 2,2,2-trifluoro-N′-hydroxyacetimidamide (218.7 mmol, 28 g) and ethyl propiolate (262.5 mmol, 25.7 g). Yield 45.2 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.32 (t, 3H), 4.31 (q, 2H), 7.03 (d, 1H), 7.60 (bs, 2H), 8.29 (d, 1H). LC-MS: [M−1]=225.34.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccco3)CC1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.1 g, 0.33 mmol) in dichloromethane (3.0 mL) was added 2-furoyl chloride (0.050 g, 0.40 mmol) followed by triethylamine (0.114 mL, 0.79 mmol). The reaction mixture was stirred for 1 h at room temperature. The organic layer was separated, washed with water (2.0 mL), dried with sodium sulfate and concentrated under vacuum. The crude product was crystallized from EtOAc and hexanes to give the desired product as a purple solid (0.08 g, 61%). M.p.=165° C.; 400 MHz 1H NMR (DMSO-d6) δ 7.89-7.85 (m, 3H), 7.78 (t, 1H), 7.57 (t, 1H), 7.02 (d, J=3.6 Hz, 1H), 6.63 (d, J=3.6 Hz, 1H), 4.24 (d, 2H), 3.13 (s, 2H), 2.15 (brs, 2H), 2.08 (brs, 2H), 1.95 (m, 2H); LCMS: 396 [M+H].
Reaction SMILES: [OH:1][C:2]1([C:14](O)=[O:15])[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.C(OCC)(=O)C.Cl>O>[OH:1][C:2]1([CH2:14][OH:15])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH2:7]1
Reactant: O=C(O)C1(O)C=CC(c2ccccc2)=CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: OCC1(O)C=CC(c2ccccc2)=CC1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 4-hydroxy-4-biphenylcarboxylic acid (2.14 g) in tetrahydroftiran (25 ml) under an argon atmosphere was added slowly 1M borane-THF complex (50 ml). The resulting mixture was stirred for 18 hours before the addition of ethyl acetate (10 ml) and water (100 ml). The resulting mixture was acidified with 2N hydrochloric acid and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated . Recrystallisation from a small volume of ethyl acetate gave 4-hydroxy-4-biphenylmethanol (580 mg): NMR (d6DMSO) δ 4.5(s,2H), 6.85(d,2H), 7.35(d,2H), 7.45-7.55(dd,4H), 9.45(s,1H); m/e 201(M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1.BrCC1(CBr)C=CC(C2C=CC=CC=2C#N)=CC1.[C:35]([O:39][C:40]([NH:42][C:43]1[C:52]([N+:53]([O-:55])=[O:54])=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47][CH3:48])=[O:46])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]([C:43]1[C:52]([N+:53]([O-:55])=[O:54])=[CH:51][CH:50]=[CH:49][C:44]=1[C:45]([O:47][CH3:48])=[O:46])[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])=[CH:5][CH:4]=1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Agent: N#Cc1ccccc1C1=CCC(CBr)(CBr)C=C1
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC(C)(C)C

Procedure:
A method according to claim 1, wherein said reaction is carried out between (1) a mixture containing 2-(4-bromomethylphenyl)benzonitrile and 2-(4,4-dibromomethylphenyl)benzonitrile and (2) methyl 2-tert-butoxycarbonylamino-3-nitrobenzoate to give methyl 2-[N-t-butoxycarbonyl-N-[(2′-cyano-biphenyl-4-yl)methyl]amino]-3-nitrobenzoate.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:25](O)[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:25]([O:1][C:2]1[C:10]2[O:9][C:8]([C:11]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[O:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:26]
Reactant: CCO
Reactant: Cc1onc(-c2ccccc2)c1C(=O)c1cc2cccc(O)c2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1cccc2cc(C(=O)c3c(-c4ccccc4)noc3C)oc12
Temperature: 0 °C
Yield: 83.6 %

Procedure:
To a solution of (7-hydroxy-2-benzofuranyl)(5-methyl-3-phenyl-4-isoxazolyl)methanone (example 4) (100 mg, 0.31 mmol) in THF (3.1 mL) was added ethanol (19 mg, 24 μL, 0.42 mmol) and triphenylphosphine (109 mg, 0.42 mmoL) at room temperature. The resulting mixture was then cooled to 0° C. and diethyl azodicarboxylate (73 mg, 65 μL, 0.42 mmol) added. The resulting mixture was maintained at 0° C. for 30 min and then allowed to warm up to room temperature overnight. The mixture was then adsorbed onto SiO2 and purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 75:25) afforded the title compound (90 mg, 83%) as a white solid. MS m/e: 348.4 [M+H]+.
Reaction SMILES: CS(OC[CH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[N:22]=3)[N:17]=[CH:16][C:15]=2[C:25](=[O:27])[CH3:26])[CH2:9][CH2:8]1)(=O)=O.N[C@H]1CC[C@H]([CH2:35][N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)CC1>>[C:25]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[CH2:12][CH2:11]1)=[N:22][C:21]([Cl:24])=[CH:20][CH:19]=2)(=[O:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H]2CC[C@H](N)CC2)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(COS(C)(=O)=O)CC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1

Procedure:
Following general procedure V, {4-[(3-acetyl-6-chloro-1,5-naphthyridin-4-yl)amino]-cyclohexyl}methyl methanesulfonate (170 mg, 0.42 mmol) was reacted with tert-butyl 4-[(trans-4-aminocyclohexyl)methyl]piperazine-1-carboxylate (93 mg, 0.50 mmol) to afford the desired product (150 mg, 73%) as a yellow solid. ESI MS m/z 502 [M+H]+
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:5]([C:20]([O:22]C)=[O:21])=[N:6][C:7]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.Cl>C1COCC1.CO>[OH:3][C:4]1[C:5]([C:20]([OH:22])=[O:21])=[N:6][C:7]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: COC(=O)c1nc(N(C)S(C)(=O)=O)c2cccnc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1nc(C(=O)O)c(O)c2ncccc12)S(C)(=O)=O
Temperature: 50 °C

Procedure:
Sodium hydroxide (2.31 mL, 2.31 mmol, 1N solution) was added to a suspension of methyl 8-hydroxy-5-[methyl(methylsulfonyl)amino]-1,6-naphthyridine-7-carboxylate (240 mg, 0.77 mmol) in a 1:1 solution of THF/methanol (5 mL) and the resulting mixture was heated overnight at 50° C. In the morning, the homogeneous solution was acidified to a pH=4 using 1N HCl solution. The reaction was cooled and the solids that had precipitated out of solution were collected by vacuum filtration to give the desired product as an off-white solid.
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].FC1C=CC([C:21](=[O:25])C(C)C)=CC=1.C[O-].[Na+]>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([O:25][CH3:21])[C:2]([CH3:13])([CH3:12])[O:4]2)=[CH:6][CH:7]=1
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1
Reactant: CC(C)C(=O)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1(c2ccc(F)cc2)OC1(C)C

Procedure:
39.22 g (0.16 mol) of 2-bromo-1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by brominating 1-(4-fluorophenyl)-2-methylpropan-1-one analogously to European Patent Application No. 3,002, are dissolved in 50 ml of methanol. 23.5 g (0.176 mol) of methanolic 30% strength sodium methylate solution are added dropwise at room temperature. The methanol is then distilled off, and the residue is taken up with diethyl ether. The salt is filtered off, and the ether solution is concentrated. The liquid crude product is further reacted as described hereinafter without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:41]([CH3:42])=[CH:40][C:12]([CH2:13][C@@H:14]([CH2:19][C:20](=[O:39])[N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:33][CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[NH:29][C:28]3=[O:38])[CH2:23][CH2:22]2)[C:15]([O:17]C)=[O:16])=[CH:11][C:10]=1[O:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>>[CH2:1]([O:8][C:9]1[C:41]([CH3:42])=[CH:40][C:12]([CH2:13][C@@H:14]([CH2:19][C:20](=[O:39])[N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[CH2:33][CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[NH:29][C:28]3=[O:38])[CH2:25][CH2:26]2)[C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Product: COc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1

Procedure:
Prepared analogously to Example 7g from 7.83 g (13.1 mmol) methyl(S)-2-(4-benzyloxy-3-methoxy-5-methyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate and 1.25 g (52.2 mmol) LiOH.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.C[O:18]B(OC)OC.C(OO)(=O)C>CCOCC.O.S(=O)(O)[O-].[Na+]>[OH:18][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: COB(OC)OC
Agent: CC(=O)OO
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Oc1cnc2ccccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
3-Bromoquinoline (5.0 g, 24.03 mmoL) was dissolved in anhydrous ether and cooled to −78° C. It was then treated with n-butyllithium (10.57 mL, 26.43 mmoL, 2.5M in hexanes) by slow addition over 30 min. The reaction was stirred at −78° C. for 30 min then it was treated with trimethylborate (2.50 g, 24.03 mmoL) by slow addition over 10-15 min. The reaction was then allowed to stir at 0° C. for 45 min then at room temperature for 15 min. The reaction was then cooled back to −78° C. and treated with peracetic acid (5.49 g, 26.44 mmoL) and stirred at room temperature for 20 hr. The reaction was diluted with H2O (40 mL) and solid sodium bisulfite was added until the peroxides were destroyed as indicated with peroxide test strips. The layers were separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The organic layer was concentrated in vacuo and the residue was azeodried with toluene (4×50 mL). The residue was triturated with toluene and the solids were collected by vacuum filtration to give 1.43 g (41%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.29 (s, 1H) 8.58 (d, J=2.57 Hz, 1H) 7.85-7.95 (m, 1H) 7.72-7.83 (m, 1H) 7.40-7.57 (m, 3H). MS m/z (DCI) 146.0 (M+H)+.
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1OCCCC(N1[C:19]2[C:14](=[C:15](C3C=NN(CC(OCC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13]CC1)=O.OCCCC(N1C2C(=C(C3C=NN(CC(OCC)=O)C=3)C=CC=2)CCC1)=O.[OH:64][CH2:65][CH2:66][CH2:67][C:68]([N:70]1[C:79]2[C:74](=[C:75]([C:80]3[CH:81]=[C:82]([CH:97]=[CH:98][CH:99]=3)[CH2:83][O:84][C:85]([NH:87][CH2:88][CH2:89][C:90]([O:92][C:93]([CH3:96])([CH3:95])[CH3:94])=[O:91])=[O:86])[CH:76]=[CH:77][CH:78]=2)[CH2:73][CH2:72][CH2:71]1)=[O:69].ClC1C=C(Cl)C(Cl)=CC=1O.C1(C)C(O)=CC=CC=1>>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:64][CH2:65][CH2:66][CH2:67][C:68]([N:70]1[C:79]2[C:74](=[C:75]([C:80]3[CH:81]=[C:82]([CH:97]=[CH:98][CH:99]=3)[CH2:83][O:84][C:85]([NH:87][CH2:88][CH2:89][C:90]([O:92][C:93]([CH3:96])([CH3:94])[CH3:95])=[O:91])=[O:86])[CH:76]=[CH:77][CH:78]=2)[CH2:73][CH2:72][CH2:71]1)=[O:69]
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(-c2cccc3c2CCCN3C(=O)CCCO)c1
Reactant: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cc(Cl)c(Cl)cc2Cl)cn1
Agent: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCO)cn1
Agent: Cc1ccccc1O
Agent: Oc1cc(Cl)c(Cl)cc1Cl
Product: Cc1ccccc1OCCCC(=O)N1CCCc2c(-c3cccc(COC(=O)NCCC(=O)OC(C)(C)C)c3)cccc21

Procedure:
The title compound was prepared using a procedure analogous to ethyl 2-(4-(1-(4-(2,4,5-trichlorophenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate except that ethyl 2-(4-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate was replaced with tert-butyl 3-((3-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzyloxy)carbonylamino)propanoate and 2,4,5-trichlorophenol was replaced with o-cresol. LCMS, [M+H]+=587.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=O.Cl.[OH-].[NH4+]>O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:12]1[NH:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[N:11]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1NC(=O)c1ccco1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(-c3ccco3)[nH]c2c1
Temperature: 0 °C

Procedure:
A stirred mixture of N-(2-amino-4-nitrophenyl)-2-furamide (125 g, 0.5 mole) in a solution of concentrated hydrochloric acid (400 m) and 850 ml of water is heated on a steam bath for 3 hr. The reaction mixture after pouring into 4 liters of ice is treated with concentrated ammonium hyroxide until basic. The intermediate is filtered to give 104 g (91 percent).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+].Cl.C(OCC)(=O)C>[OH:1][C:2]1[C:11]([CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[C:10]([O:17][CH3:18])[CH:9]=[C:8](/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)OC)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: C=C(C)CCc1c(OC)cc(/C=C/c2ccccc2)c(C(=O)O)c1O
Yield: 90.4 %

Procedure:
Dissolve compound 8 (3 g, 0.0085 mol) in 30 ml 20% aqueous sodium hydroxide solution, heat to reflux for 2 h, cool the solution to stop the reaction. Add in 10% dilute hydrochloric acid to adjust the pH to less than 2 to cause a formation of a large amount of white precipitation, filter and dry the precipitation to obtain a white solid, dissolve it in petroleum ethe/ethyl acetate and recrystallize to obtain 2.6 g white solid (90%). 1H-NMR (400M, CDCl3) δ (ppm): 1.61 (s, 3H), 1.71 (s, 3H), 3.24 (d, J=6.8 Hz, 2H), 3.91 (s, 3H), 5.12 (t, J=6.8 Hz, 1H), 6.78 (s, 1H), 7.00 (d, J=16 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 7.38 (t, J=7.2 Hz, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.84 (d, J=16 Hz, 1H), 12.28 (s, 1H). ESI-MS mz: 361.14318 [M+Na]+ (Calcd. for C21H22O4Na: 361.14158).