Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:12]=3)=[CH:9][N:8](S(C3C=CC=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Li+]>O1CCCC1.CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(Br)cnc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(-c2c[nH]c3ncc(Br)cc23)cc(NC2CCCCC2)n1
Yield: 83.2 %

Procedure:
A solution of Example 171a (0.100 g, 0.16 mmol) in 9 mL tetrahydrofuran/methanol (2:1) was treated with 1N lithium hydroxide (0.024 g, 1.00 mmol) in 1 mL water at room temperature for 16 hours. The material was diluted with water and resulting precipitate collected by filtration. Trituration with dimethyl sulfoxide/methanol and filtration afforded 54 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.11-1.44 (m, 5H) 1.54-1.66 (m, 1H) 1.67-1.80 (m, 2H) 1.87-1.99 (m, 2H) 3.62-3.77 (m, 1H) 6.78 (d, J=7.93 Hz, 1H) 6.86 (d, J=4.36 Hz, 2H) 8.23 (s, 1H) 8.37 (s, 1H) 8.49 (s, 1H) 12.41 (s, 1H). MS (ESI−) m/z 405.1 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH2:7]1)=[O:5])C.C(OC(N1CCC(N)CC1)=O)(C)(C)C.N(C(C)C)=C=O.[OH-].[Li+].O>C1COCC1>[C:36]([N:8]1[CH2:9][CH2:10][C@H:11]([NH:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)(=[O:40])[CH2:37][CH2:38][CH3:39]
Reactant: CCCC(=O)N1CC[C@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](C(=O)OCC)C1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)N=C=O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)N1CC[C@H](NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C)c3ccccc23)[C@H](C(=O)O)C1

Procedure:
(±)-(cis)-1-Butyryl-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-3-carboxylic acid ethyl ester was made following general procedure in Scheme 5, substituting (±)4-amino-1-benzyl-piperidine-3-carboxylic acid ethyl ester (5) for 4-amino-piperidine-1-carboxylic acid tert-butyl ester and substituting butyl chloride for 2-isocyanato-propane. To the solution of (±)-(cis)-1-butyryl-4-[4-(2-methyl-benzoylamino)-naphthalene-1-sulfonylamino]-piperidine-3-carboxylic acid ethyl ester (70 mg, 0.12 mmol) in THF (5 mL), was added lithium hydroxide in water solution (6 mg, 0.25 mmol) and the resultant solution was stired at 25° C. for 2 h. The reaction mixture was extracted with CH2Cl2. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide the crude product. HPLC purification of the residue gave the title compound. 1H NMR (300 MHz, DMSO) δ 10.62 (s, 1H), 8.77 (t, 1H), 8.24 (m, 3H), 7.95 (d, 1H), 7.70 (m, 3H), 7.38 (m, 3H), 3.72 (m, 2H), 3.35 (m, 6H), 3.12 (m, 1H), 2.60 (m, 1H), 2.15 (m, 2H), 1.32 (m, 4H), 0.80 (dd, 3H); LC/MS nm/z 539 (M+H)+
Reaction SMILES: ClC1C=C(C2C=C(C([N:22]3C[CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=O)OC=2C2C=CC(F)=CC=2)C=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50]([OH:52])=O)[O:40][C:41]=2[C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]#[N:49])[CH:43]=2)[CH:33]=[C:34]([F:36])[CH:35]=1>>[Cl:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]=[C:39]([C:50]([N:22]3[CH2:23][C:24](=[O:28])[NH:25][CH2:26]3)=[O:52])[O:40][C:41]=2[C:42]2[CH:43]=[C:44]([C:48]#[N:49])[CH:45]=[CH:46][CH:47]=2)[CH:33]=[C:34]([F:36])[CH:35]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccc(F)cc3)o2)CCN1
Reactant: N#Cc1cccc(-c2oc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Product: N#Cc1cccc(-c2oc(C(=O)N3CNC(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 6 starting with the compound from Example 20A and the compound from Example 35A. 1.1 equivalents of the compound from Example 35A are used. 42.0 mg (70% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:17])[CH:8]=[CH:9][C:10]2=NO)([O-:4])=[O:3].[OH2:18]>O.O.O.O.[Fe](Cl)Cl>[N+:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7](=[O:17])[CH:8]=[CH:9][C:10]2=[O:18])([O-:4])=[O:3]
Reactant: O
Reactant: O=C1C=CC(=NO)c2cccc([N+](=O)[O-])c21
Agent: Cl[Fe]Cl
Agent: Cl
Product: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
120 ml of 37 percent by weight aqueous hydrochloric acid and 42 g (0.21 mol) of iron (II) chloride tetrahydrate are introduced into a reaction vessel and saturated with approximately 8 g of gaseous hydrogen chloride. 11 g of 5-nitro-1,4-naphthoquinone-1-oxime are introduced at a temperature of about 20° to 25°C. The reaction mixture is kept at the temperature indicated with stirring and, after 2 hours, is poured into 1,000 ml of water heated to approximately 40°C. followed by stirring for 30 minutes. The reaction product precipitated is then filtered off under suction, washed with water until neutral and dried at approximately 50°C. 5-Nitro-1,4-naphthoquinone melting at 161°C is thus obtained in a yield of 9.8 g (96 percent of the theoretical yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]([CH3:67])[CH2:57][CH2:58][O:59][C:60]1[CH:65]=[CH:64][C:63]([OH:66])=[CH:62][CH:61]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:66][C:63]3[CH:64]=[CH:65][C:60]([O:59][CH2:58][CH2:57][N:56]([CH3:67])[CH3:55])=[CH:61][CH:62]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CN(C)CCOc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
The title compound 75 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 75B: 1H NMR (DMSO-d6): δ 12.85 (s, 1H), 9.58 (s, 1H), 8.03 (d, J=7.67 Hz, 1H), 7.79 (d, J=7.67 Hz, 1H), 7.67 (d, J=7.06 Hz, 1H), 7.33-7.50 (m, 4H), 6.86-6.93 (m 4H), 4.83 (s, 2H), 4.21-4.24 (m, 2H), 3.92 (t, J=6.29 Hz, 2H), 3.73 (t, J=5.98 Hz, 2H), 3.15-3.18 (m, 2H), 3.03 (t, J=5.98 Hz, 2H), 2.85 (s, 6H), 1.94-2.01 (m, 2H). ESI (+)/MS: 658 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:23][CH:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[CH:13]1[CH:9]([CH2:10][CH:11]([O:26][C:27]3[C:36]4[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=4)[N:30]=[C:29]([C:39]4[S:40][CH:41]=[C:42]([CH:44]([CH3:46])[CH3:45])[N:43]=4)[CH:28]=3)[CH2:12]1)[C:8](=[O:47])[NH:7]2)=[O:5])C.[Li+].[OH-].Cl>O1CCOCC1.CO>[CH:44]([C:42]1[N:43]=[C:39]([C:29]2[CH:28]=[C:27]([O:26][CH:11]3[CH2:10][CH:9]4[CH:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][CH:22]5[C:6]([C:4]([OH:5])=[O:3])([NH:7][C:8]4=[O:47])[CH2:23]5)[CH2:12]3)[C:36]3[C:31](=[CH:32][C:33]([O:37][CH3:38])=[CH:34][CH:35]=3)[N:30]=2)[S:40][CH:41]=1)([CH3:46])[CH3:45]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4nc(C(C)C)cs4)nc4cc(OC)ccc34)CC1C(=O)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 17-[2-(4-isopropyl-thiazol-2-yl)-7-methoxy-quinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (34, 182 mg, 0.275 mmol) in dioxane (3 mL) and MeOH (1.5 mL) was added a 1 M aqueous solution of LiOH (3 mL). After 72 h, the reaction mixture was successively acidified to pH 2 with 1.7 M HCl and evaporated under vacuum. Then, 1 g of silica was added towards the end to adsorb the crude product. Purification by flash column chromatography (15 g YMC silica; gradient MeOH/CH2Cl2: 200 mL each 2%, 4%, 6%, 100 mL each 8%, 10%; forefraction 100 mL followed by 15-mL fractions, desired product fractions 33-42) gave 164 mg (94%) of the title product 35 as a yellow solid: Rf (10% MeOH—CH2Cl2)=0.38.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:31][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][CH:21]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 74.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (89 mg) and 4-hydroxyphenyl 4-methylphenyl ketone (248 mg) obtained in Example 25 were mixed and stirred at 180° C. for 10 minutes, and the reaction mixture was then purified in the same manner as described in Example 24 to obtain 118 mg of the title compound (yield: 74%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1.C=O.[C:34](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[CH3:34][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])[CH:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[O:9])[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCNCC3)c2)ccn1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCN(C)CC3)c2)ccn1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
5-(2-(3-Ethylureido)pyridin-4-yloxy)indole-1-carboxylic acid piperidin-4-ylamide (36 mg, 0.085 mmol, Example 181) was dissolved in tetrahydrofuran (2.0 ml) and methanol (1.0 ml); and a 37% aqueous formaldehyde solution (0.036 ml, 0.43 mmol) and acetic acid (0.0098 ml, 0.17 mmol) were added thereto. While stirring at room temperature, sodium triacetoxyborohydride (27 mg, 0.13 mmol) was added; and the reaction mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate; and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; the obtained crystals were suspended in diethyl ether, filtered off, washed with diethyl ether, and dried to yield the title compound (25 mg, 0.057 mmol, 67%) as colorless crystals.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:39])([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[CH3:33]>>[CH3:31][C:32]([NH:39][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)[CH3:33]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CC(C)(N)c1cccs1
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1cccs1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-methyl-1-(2-thienyl)ethylamine (prepared as described in Preparation 11a) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 88%.
Reaction SMILES: CC1C=C(C2C=CC(C)=CC=2)SC=1C(O)=O.C=O.S(Cl)(Cl)=O.Cl[CH2:24][CH2:25][C:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[S:28][C:27]=1[C:38](Cl)=[O:39].[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:52][CH2:51][C@@H:50]([N:53]([CH3:55])[CH3:54])[CH2:49]2)=[CH:44][CH:43]=1>>[CH3:54][N:53]([CH3:55])[C@@H:50]1[CH2:51][CH2:52][N:48]([C:45]2[CH:46]=[CH:47][C:42]([N:41]3[CH2:24][CH2:25][C:26]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[S:28][C:27]=4[C:38]3=[O:39])=[CH:43][CH:44]=2)[CH2:49]1
Reactant: Cc1ccc(-c2cc(CCCl)c(C(=O)Cl)s2)cc1
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Agent: C=O
Agent: Cc1ccc(-c2cc(C)c(C(=O)O)s2)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(N4CC[C@@H](N(C)C)C4)cc2)CC3)cc1

Procedure:
Firstly 3-methyl-5-p-tolylthiophene-2-carboxylic acid was reacted with paraformaldehyde by method C1, and then the product was treated with thionyl chloride by method B. The resulting 3-(2-chloroethyl)-5-p-tolylthiophene-2-carbonyl chloride was finally reacted with [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method A. The product with the molecular weight of 431.60 (C26H29N3OS) was obtained in this way; MS (ESI): 432 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16](Br)=[N:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:26][C:22]3[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[N:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)cnc2Br)ccn1
Reactant: Nc1cncc(Cl)c1
Product: Cc1cc(NC(=O)c2nc(C)cnc2Nc2cncc(Cl)c2)ccn1

Procedure:
The title compound, MS: m/e=355.1 (M+H+), was prepared in accordance with the general method of example 4, step 2 from 3-bromo-6-methyl-pyrazine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide and 5-chloropyridine-3-amine.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([OH:8])=[CH:6][CH:7]=1.[CH:10](O)([CH3:12])[CH3:11]>>[Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5]([O:8][CH:10]([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: Cc1nc(O)ccc1Br
Product: Cc1nc(OC(C)C)ccc1Br

Procedure:
The title compound was prepared from 3-bromo-6-hydroxy-2-methylpyridine and isopropanol in analogy to Example 9c): colorless liquid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[O:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]OS(C)(=O)=O)=[CH:35][C:34]=1[Cl:45])[Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[O:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:35][C:34]=1[Cl:45])[Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](OCc1ccc(COS(C)(=O)=O)cc1Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(COc2ccccc2)cc1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
To a solution of phenol (969 mg) in N,N-dimethylformamide (27 ml) was added potassium carbonate powder (1.92 g) and the mixture was stirred at room temperature for 5 min. 1-((tert-Butyldiphenylsiloxy)methyl)-2-chloro-4-((methanesulfonyloxy) methyl)benzene (3.39 g) was added and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was allowed to cool to room temperature. Water was added and the mixture was extracted twice with hexane. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/1) to give 1-((tert-butyldiphenylsiloxy)-methyl)-2-chloro-4-(phenoxymethyl)benzene (2.65 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][O:21][CH3:22])=[C:7]([CH:18]=1)[CH:8]=[N:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][O:21][CH3:22])=[C:7]([C:8]2[O:17][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([CH3:16])[C:10]=3[N:9]=2)[CH:18]=1
Reactant: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Solvent: c1ccccc1
Product: COCOc1ccc(OC)cc1-c1nc2c(C)cccc2o1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
A solution of 2-[(5-methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) (1.51 g, 5 mmol) and BaMnO4 (5.13 g, 20 mmol) in benzene (50 mL) was refluxed for 5 hours under dry N2 gas flowing. After the reaction mixture was cooled to room temperature, BaMnO4 was removed through Celite and the filtrate was concentrated in vacuo. The black residue was purified by silica gel column chromatography (CHCl3) to afford the objective compound as a pale yellow solid (976 mg, 65%): 1H-NMR (500 MHz, CDCl3) , 2.68 (s, 3H), 3.55 (s, 3H), 3.87 (s, 3H), 5.25 (s, 2H), 7.02 (dd, 1H, J=9.0, 3.0 Hz), 7.15 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=9.0 Hz), 7.24 (t, 1H, J=8.0 Hz), 7.42 (d, 1H, J=8.0 Hz), 7.63 (d, 1H, J=3.0 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[CH:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[CH:35][CH:34]=[N:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1cccc(Cn2cccn2)c1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3cccn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-pyrazol-1-ylmethyl)aniline (Flrochem, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16]>>[CH2:8]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCCCC
Reactant: Oc1ccccc1
Product: CCCCCCCCCc1ccc(O)cc1
Reaction time: 20 h
Yield: 92 %

Procedure:
A suspension of 190 parts of phenol, 152 parts of propylene trimer and 7 parts of ion exchange resin is prepared in a stirred reactor at 120° C. and 1 bar pressure, the mixture being stirred at 500 rpm. The ion exchange resin is a sulfonated styrene/divinylbenzene copolymer resin, which has been dehydrated under reduced pressure for 20 hours at 100° C. before being used; it has a gel structure and its particle size is from 20 to 150 micrometers. The suspension is then stirred constantly in the reactor at 500 rpm. After 6 hours, 12.1 parts of phenol and 9.8 parts of propylene trimer are introduced per hour at 120° C. and 1 bar pressure and correspondingly 21.9 parts per hour of suspension are filtered through a suction line equipped with a metal filter (pore diameter 10 micrometers) and are subjected to fractional distillation. After 200 hours' operation, 3,145 parts (92% of theory, based on starting material II) of 4-nonylphenol of boiling point 175°-180° C./27 millibars are obtained. The conversion is 57%, based on phenol employed, or 95% based on starting material II.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:15]([O-])(=[O:18])[C:16]#[CH:17].[Na+].S(Cl)(Cl)=O.[C:25]([Cl:29])(=[O:28])[C:26]#[CH:27]>C1C=CC=CC=1>[C:25]([Cl:29])(=[O:28])[C:26]#[CH:27].[C:15]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[C:16]#[CH:17]
Reactant: OCCCCCc1ccccc1
Reactant: C#CC(=O)[O-]
Agent: C#CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: C#CC(=O)OCCCCCc1ccccc1

Procedure:
With stirring, 1 gram of 5-phenylpentanol was added dropwise to a mixture of 0.25 g of sodium hydride (60% oil suspension) and 25 ml of dried benzene. The mixed solution is further stirred at ambient temperatures for one hour. A benzene solution of propiolic acid chloride is prepared by stirring a mixture of 0.62 g of sodium propiolate, 0.80 g of thionyl chloride, and 20 ml of dried benzene at ambient temperatures for five hours. The benzene solution of propiolic acid chloride thus prepared is added to the mixed solution, stirred at ambient temperatures for five hours, and refluxed for one hour. After the reaction is completed, the reaction solution is washed successively with water and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue is subjected to silicagel column chromatography to yield 5-phenylpentyl propiolate (compound 1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17]CC)=O.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:15]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=3)=[O:17])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cnc2ccc([N+](=O)[O-])cc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc([N+](=O)[O-])cc2c1O
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 0.65 g of ethyl 4-hydroxy-6-nitro-3-quinolinecarboxylate (J. Amer. Chem. Soc., 68, 1264 (1946)) and 5.0 mL of 4-chlorobenzylamine is stirred 1 hour at 200° C. The mixture is cooled to 25° C. and it is diluted with 25 mL of hexanes. After stirring for an additional 1 h the solid precipitate is collected by filtration and washed with 10 mL of hexanes. It is dried in a stream of air and then it is suspended in 20 mL of glacial acetic acid. The mixture is heated until the solid is completely dissolved and the resulting solution is diluted with 200 mL of distilled water. The mixture is allowed to cool to 25° C. and the solid is collected by filtration. It is washed with a small volume of 10% aqueous acetic acid and then it is dried at torr and 45° C. for 18 h. The yield is 0.41 g.