Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])SC)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25](=[O:66])[NH:26][C:27]([C:29]1[S:30][C:31]([S:64][CH3:65])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([NH2:50])=[CH:45][C:44]=3[NH:51][C:52]([NH:54][CH2:55][CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:53])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:33]=1)=[NH:28])([CH3:23])([CH3:22])[CH3:21]>CO.C(O)(=O)C>[C:20]([O:24][C:25](=[O:66])[NH:26][C:27]([C:29]1[S:30][C:31]([S:64][CH3:65])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[C:48]([CH3:49])=[CH:47][C:46]([NH:50][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[CH:45][C:44]=3[NH:51][C:52]([NH:54][CH2:55][CH2:56][NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:53])[CH:40]=[CH:41][CH:42]=2)(=[O:35])=[O:36])[CH:33]=1)=[NH:28])([CH3:22])([CH3:23])[CH3:21]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)NCCNc2ccccc2)c1
Solvent: CC(=O)O
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2NC(=O)NCCNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
1,3-Bis-t-butoxycarbonyl-2-methyl-2-thiopseudourea (0.033 g, 0.114 mmol) was added to a solution of [(4-{4′-amino-6′-methyl-2′-[3-(2-phenylamino-ethyl)-ureido]-biphenyl-3-sulfonyl}-5-methylsulfanyl-thiophen-2-yl)-imino-methyl]-carbamic acid tert-butyl ester [example 216, step a] in methanol [1 mL] and 1 drop of acetic acid. The reaction was stirred at room temperature for 1 hour and evaporated. The reaction was evaporated and column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.072 g, 68%) as a solid. ESI-MS (m/z): Calcd. for C44H56N8O9S3: 936.33; found: 936.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:40])[C:30]2[C:25](=[CH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[C:22]([CH3:40])([CH3:21])[CH2:23][CH2:24]4)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Reactant: CC1(C)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 102 starting from 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (US 2005/176722) and 2-(1,1-dimethylindan-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](SC)=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CO>[NH2:11][C:10]1[NH:20][N:19]=[C:8]([NH:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]#[N:13]
Reactant: NN
Reactant: CSC(NCc1ccc(N)cc1)=C(C#N)C#N
Solvent: CO
Solvent: O
Product: N#Cc1c(NCc2ccc(N)cc2)n[nH]c1N
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 15.71 g (64.3 mmol) of 3-(4-amino-benzylamino)-2-cyano-3-methylmercapto-acrylonitrile, 3.35 ml (67.5 mmol) of hydrazine hydrate and 90 ml of methanol is stirred for 1 hour at 20° C., heated under reflux for 4 hours and then concentrated by evaporation in vacuo. Digestion of the crystalline residue in 70 ml of diisopropyl ether, filtering and digestion again in 100 ml of isopropanol yield the title compound; m.p. 168-170° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][C:13]([F:16])([F:15])[F:14])[CH:5]=1)([O-])=O.Cl>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][C:13]([F:14])([F:15])[F:16])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1OC(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc(N)cc1OC(F)(F)F
Reaction time: 17 h

Procedure:
To a stirred solution of 4-nitro-2-trifluoromethoxyanisole (500 mg, 2.11 mmol) in MeOH (8.0 mL) at room temperature was added aqueous HCl solution (1.0 mL, 3.0 M) followed by 10% Pd/C (80 mg). The reaction mixture was stirred under H2 atmosphere for 17 h, filtered through a pad of celite and concentrated to give 4-amino-2-trifluoromethoxyanisole as a hydrochloride salt (500 mg). The product was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[NH2:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1cc(Br)cnc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cc(-c2ccccc2)cnc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-3-amino-2-nitropyridine (190 mg, 0.872 mmol) in a dry microwave reaction tube were added phenylboronic acid (159 mg, 1.31), K2CO3 (361 mg, 2.61 mmol) and Pd(PPh3)4 (101 mg, 0.087 mmol) and the reaction flask was evacuated and flushed with N2 four times. To this solid reaction mixture was added anhydrous THF (2 mL) and the reaction mixture was degassed by applying vacuum and flushing with N2 five times and sealed in N2 atmosphere. The reaction mixture was then heated 120° C. for 2 h. After this time, LC/MS analysis of the reaction mixture should essentially show the desired product. Reaction mixture was concentrated in vacuo and to the residue was added MeOH and stirred for 30 min. All the solids were collected by filtration and washed thoroughly with MeOH and water MS: cal'd 216 (M+H)+, exp 216 (M+H)+
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=O)([OH:3])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:26]1(=[O:32])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:29](=[O:31])[CH:28]=[CH:27]1
Reactant: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O

Procedure:
A mixture of N-(21-carboxyheneicosyl)maleamic acid (450 mg, 0.99 mmoles), 2.8 ml of acetic anhydride, and anhydrous sodium acetate (40.7 mg, 0.50 mmoles) was reacted at 100° C for 1 hour. After the completion of reaction, the reaction mixture was treated in the sane manner as in Example 1, to give 22-maleimidodocosanoic acid having the following properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Product: CCOC(=O)NCC(c1ccccc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97 %

Procedure:
To 4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (1.0 g, 3.09 mmol) was added ethyl chloroformate (15 mL) and the reaction mixture is allowed to reflux for 18 h. The reaction mixture is then concentrated to dryness yielding 1.05 g (97%)product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.O=S(Cl)[Cl:19]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([Cl:19])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CN2CCOCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Yield: 105 %

Procedure:
2.33 g of α-morpholinoparatoluic acid are placed in 30 mL of CH2Cl2 and 3.76 g of SOCl2 are added. The not very homogenous solution is taken to reflux for 48 hours The white precipitate obtained is filtered, washed with CH2Cl2 and dried. 2.65 g of product is obtained (Yield=70%).
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:33])([CH3:32])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][CH2:30][O:31][C:24]=4[CH:23]=3)[N:15]=2)=[CH:9][CH:8]=1)=O)C.CC(C[AlH]CC(C)C)C>>[CH2:30]1[CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:16]3[N:15]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([C:6]([CH3:32])([CH3:33])[CH2:4][OH:3])=[CH:8][CH:9]=4)[C:19]([F:20])=[CH:18][N:17]=3)=[CH:23][C:24]=2[O:31]1
Reactant: CCOC(=O)C(C)(C)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(CO)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1

Procedure:
In like manner to the preparation of N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4(2-hydroxy-1,1-dimethylethyl)phenyl]-pyrimidine-2,4-diamine, N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine was reduced with DIBALH to give N2-(3,4-ethylenedioxyphenyl)-5-fluoro-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.23 (s, 1H), 8.94 (s, 1H), 8.01 (d, 1H, J=3.5 Hz), 7.63 (d, 2H, J=8.8 Hz), 7.31-7.27 (m, 3H), 6.98 (dd, 1H, J=2.9 and 8.8 Hz), 6.65 (d, 1H, J=8.8 Hz), 4.65 (t, 1H, J=5.3 Hz), 4.17-4.16 (m, 4H), 3.39 (d, 2H, J=5.2 Hz), 1.20 (s, 6H). 8.9 Hz), LCMS: ret. time: 19.52 min.; purity: 100%; MS (m/e): 411 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH:43]([OH:47])[CH2:44][CH2:45][CH3:46])[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:47][CH:43]([CH2:42][CH2:41][N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)[CH2:44][CH2:45][CH3:46])=[CH:18][CH:17]=1
Reactant: CCCC(O)CCN1CCOCC1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(CCN1CCOCC1)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 89.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-morpholino-3-hexanol (49 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (77 mg, yield 73%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].C1N=C[N:23](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-]>CN(C=O)C>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[CH:9]=[N:8]1)([CH3:6])[C:3]([NH2:23])=[O:4]
Reactant: CC(C)(C(=O)O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)n1cc(-c2ccnc3[nH]ccc23)cn1
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A mixture of 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanoic acid (23 mg, 0.000085 mol) and N,N-carbonyldiimidazole (CDI) (21 mg, 0.00013 mol) in 2 mL of DMF was stirred for 3 hours. An excess of solid NH4Cl and TEA was added to the mixture and this was stirred for 3 hours. The majority of solvent was removed in vacuo, and the crude residue was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) followed by re-purification via preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford 2-methyl-2-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]propanamide (6 mg, 26%). 1H NMR (400 MHz, d6-DMSO): 11.63 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.21 (s, 1H), 6.93 (s, 1H), 6.80 (dd, 1H), 1.77 (s, 6H); MS (ES): 270 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([CH2:13][NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][C:8]=2[CH:7]=1.[OH2:26].FC(F)(F)C(O)=O.C(#[N:36])C>>[OH:26][NH:36][C:3](=[O:2])[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][C:9]2[N:10]([CH3:22])[C:11]([CH2:13][NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: O
Reactant: CC#N
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CNCc1ccccc1)n2C
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CNCc2ccccc2)nc2cc(C=CC(=O)NO)ccc21

Procedure:
The titled compound (60) was prepared according to the procedures described in Step 4 of Example 1, by using 3-[2-(benzylamino-methyl)-1-methyl-1H-bezimidazol-5-yl]-acrylic acid methyl ester as the starting material HPLC: 89.6%; tR=(LC/PDA: Phenomenex Luna C18 2.0×150 mm 5μ column; 0.8 mL/min, gradient 5-65% B over 15.5 min, Solvent A: H2O with 0.1% trifluoroacetic acid; Solvent B: Acetonitrile with 0.1% trifluoroacetic acid; UV 254): 3.68 min. 1H NMR (400 MHz, DMSO-d6) δ 3.78 (3H, s), 4.37 (2H, s), 4.58 (2H, s), 6.48 (1H, d), 7.46 (3H, m), 7.55 (3H, m), 7.64 (2H, t), 7.88 (1H, s), 9.88 (1H, bs), 10.74 (1H, bs). MS (m/z): 337 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Br.[OH-:18].[K+]>C(O)C.O>[Br:1][C:2]1[C:3](=[O:17])[N:4]([C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:18]
Reactant: [OH-]
Reactant: O=c1c(Br)c(Br)cnn1-c1cc(F)cc(F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1c(Br)c(O)cnn1-c1cc(F)cc(F)c1

Procedure:
4,5-Dibromo-2-(3,5-difluorophenyl)pyridazin-3-one (1.5 g, 0.0041 moles) was suspended in ethanol (50 ml) and potassium hydroxide (0.8 g, 0.0123 moles) was added in water (8 ml). Refluxed for 4 hours with stirring. Evaporated to a low bulk and diluted with water. Acidified to pH2 with conc. hydrochloric acid and extracted with ethyl acetate. Washed with water and dried with anhydrous magnesium sulphate. Filtered and evaporated the filtrate to give an orange solid. Triturated with diethyl ether and dried in a desiccator to give the product as a cream solid. (0.7 g, 56%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7].[CH:42](=[O:44])[CH3:43]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:6]([C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)[C:11](=[O:21])[N:12]2[C:17]=1[C:16]1[S:18][C:19]([CH:42]([OH:44])[CH3:43])=[CH:20][C:15]=1[CH:14]=[CH:13]2)=[O:7]
Reactant: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1
Reactant: CC=O
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3cc(C(C)O)sc3c12)c1ccccc1

Procedure:
By lithiation of 8-(4-benzyloxy-phenyl)-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid (2-methoxy-ethyl)-phenyl-amide and reaction with acetaldehyde.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8].CN(C=O)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(O)c(O)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium hydroxide (6.4 g) in water (40 ml) was added to a mixture of 3,4-dihydroxybenzoic acid (24.8 g) and DMF (200 ml) which had been cooled in an ice-bath. The mixture was stirred for 20 minutes and then benzyl bromide (19.1 ml) was added dropwise. After the addition was complete, the mixture was allowed to reach ambient temperature and was stirred for 20 hours. The mixture was then warmed to 50° C. for 2 hours. The solvent was removed by evaporation and the residue was partitioned between water (300 ml) and ethyl acetate (100 ml). The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined ethyl acetate extracts were washed with water (100 ml), saturated sodium hydrogen carbonate solution (100 ml), water (100 ml) and with saturated sodium chloride solution (100 ml) and dried (MgSO4). The solvent was removed by evaporation to give a brown solid which was crystallised from toluene to give benzyl 3,4-dihydroxybenzoate (19 g) as a solid; m.p. 147°-149° C.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH2:30])=[C:14]([O:16][CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[C:26]([F:29])([F:28])[F:27])[CH3:18])[CH:15]=2)=[CH:6][CH:5]=1.O.[Li+].[OH-]>CC(O)C.CCOC(C)=O>[NH2:30][C:13]1[N:12]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[CH:5][CH:6]=2)=[CH:15][C:14]=1[O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[C:26]([F:29])([F:28])[F:27])[CH3:18]
Reactant: COC(=O)c1ccc(-c2cnc(N)c(OC(C)c3cccc(F)c3C(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(Oc1cc(-c2ccc(C(=O)O)cc2)cnc1N)c1cccc(F)c1C(F)(F)F
Yield: 87.5 %

Procedure:
To a stirred solution of 4-{6-amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid methyl ester (1.4 g, 3.2 mmol) in warm IPA (72 mL) was added H2O (38 mL) containing LiOH (0.68 g, 16.2 mmol). The reaction was heated to reflux for 3.5 hr. The reaction was neutralized and diluted with EtOAc (200 mL) and extracted upon cooling. The organic layer was washed with brine (50 mL), dried over Na2SO4 and concentrated under vacuum to yield 4-{6-Amino-5-[1-(3-fluoro-2-trifluoromethyl-phenyl)-ethoxy]-pyridin-3-yl}-benzoic acid (1.2 g, 2.8 mmol, 88%). 1H NMR (MeOD, 300 MHz) δ 1.75 (d, 3H, J, 6.2 Hz), 4.88-4.93 (m, 1H), 7.01 (d, 1H, J, 1.8 Hz), 7.39 (d, 2H, J, 8.3 Hz), 7.52-7.67 (m, 3H), 7.80 (d, 1H, J, 1.8 Hz), 7.97 (d, 2H, J, 8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH:14]=[O:15])=[C:12]([C:16](Cl)=O)[O:11][N:10]=1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:43])[CH:39]([CH2:41]C)[CH3:40])[CH:34]=[CH:35][CH:36]=2)[CH2:27][CH2:26]1>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([C:14]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:43])[CH:39]([CH3:40])[CH3:41])[CH:32]=3)[CH2:29][CH2:30]2)=[O:15])=[C:12]([CH3:16])[O:11][N:10]=1
Reactant: O=Cc1c(-c2c(Cl)cccc2Cl)noc1C(=O)Cl
Reactant: CCC(C)C(=O)Nc1cccc(C2CCN(CCCCCN)CC2)c1
Solvent: C1CCOC1
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)NCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.2 %

Procedure:
A mixture of 3-(2,6-dichlorophenyl)-4-formyl-5-isoxazolecarbonyl chloride (69.0 mg, 0.250 mmol), N-{3-[1-(5-aminopentyl)-4-piperidinyl]phenyl}-2-ethylpropanamide (44.0 mg, 0.150 mmol), TEA (30.0 mg, 0.300 mmol) in THF (2 mL) was stirred for 12 h at room temperature. The crude product was purified by preparative TLC using CH2Cl2/MeOH/isopropyl amine (19:1:0.2) to give the desired product (52 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 7.52-7.49 (m, 2H), 7.49-7.41 (m, 2H), 7.39-7.31 (m, 2H), 7.29-7.21 (m, 2H), 6.92 (d, 1H, J=7.6 Hz), 3.25-3.11 (m, 5H), 2.81-2.74 (m, 4H), 2.58-2.44 (m, 4H), 2.30-2.19 (m, 2H), 1.93-1.78 (m, 4H), 1.56-1.44 (m, 2H), 1.31-1.28 (m, 2H), 1.24 (d, 6H, J=6.6 Hz); ESMS m/e: 585.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.N.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]=1[NH2:1]
Reactant: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCn1c(N)c(N)c(=O)[nH]c1=O
Reaction time: 0.33 h
Yield: 85.1 %

Procedure:
To a mixture of 6-amino-5-nitroso-1-pentylpyrimidine-2,4(1H,3H)-dione (1.9 g, 8.3 mmol) and a solution of ammonia in water (20 M, 20 mL) at 70° C. was added sodium dithionite (3.1 g, 18 mmol) slowly. After stirring for 20 minutes, the reaction mixture was concentrated to a volume of about 10 mL and cooled in an ice bath. The greenish solid was collected by filtration and dried on high vacuum for 4 h to provide the desire product (1.5 g, 85% yield). LCMS calculated for C9H17N4O2 (M+H): 213.1. found: 213.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[S:12][C:13]([CH2:17][NH2:18])=[C:14]([CH3:16])[N:15]=1>>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:18][CH2:17][C:13]2[S:12][C:11]([CH3:10])=[N:15][C:14]=2[CH3:16])[CH:7]=1
Reactant: Cc1nc(C)c(CN)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Product: Cc1nc(Cl)cc(NCc2sc(C)nc2C)n1

Procedure:
The title compound was prepared from 4,6-dichloro-2-methylpyrimidine and (2,4-dimethylthiazol-5-yl)methanamine according to the protocol outlined in Example 1, to afford 3A-1 as a solid. LRMS (ES) (M+H)+: observed=269.1, calculated=269.7.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:11][CH3:12])=[CH:6][CH:5]=2.Br[CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>O1CCOCC1.CCOC(C)=O.[Ag-]=O>[CH3:12][O:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[CH2:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccccc1CBr
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Cc1c(C)[nH]c2ccc(OC)cc12
Temperature: 50 °C
Yield: 21.2 %

Procedure:
A mixture of 2-methyl-5-methoxy indole (1.01 g, 6.2 mmol), methyl 2-(bromomethyl)benzoate (1.60 g, 6.9 mmol) and silver (I) oxide (1.59 g, 6.9 mmol) in dioxane (8 mL) was heated to 50° C. for 20 h. The mixture was cooled, diluted with EtOAc and filtered thorugh celite. The filtrate was concentrated and the resulting residue was chromatographed to give 406 mg of the title compound.