Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13].[OH-].[K+]>C1C=CC=CC=1.C(O)C>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)CCCCNc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)CCCCNc1ccccc1-c1ccccc1
Reaction time: 24 h
Yield: 77.3 %

Procedure:
A solution of 8.0 g of ethyl 5-(biphenyl-2-yl)amino-valerate (see Example 53) in 60 ml of benzene is mixed with a solution of 2.2 g of potassium hydroxide in 20 ml of ethanol. After allowing the resulting admixture to stand for 24 hours at room temperature, the solvent mixture is distilled off in vacuo. The residue is then dissolved in water; the obtained aqueous solution is washed with diethyl ether and then acidified with dilute hydrochloric acid. The formed precipitate, which is oily at first, is taken up in dichloromethane. The solvent is then distilled off and the residue recrystallized from ethyl acetate/petrol ether (1:1) to obtain 5.6 g (77.3% of theory) of 5-[N-(biphenyl-2-yl)amino]valeric acid, MP 73° to 75°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][C:10]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH2:29][CH2:30][CH3:31]>C(O)C.C(O)(=O)C>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]1[C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[CH:11][C:10]=2[N:26]=[C:28]1[CH2:29][CH2:30][CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)CNc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
The product from step c.) (100 mg, 0.25 mmol) was dissolved in ethanol (5 mL) and treated with acetic acid (2 drops) followed by butyraldehyde (35 uL, 0.39 mmol). The reaction was heated to 70° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude sub-title compound that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])=[N:9][NH:8][C:7]2=[O:22].[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH2:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([N:28]3[CH2:29][CH2:30][CH:25]([O:24][CH3:23])[CH2:26][CH2:27]3)=[O:17])[CH:14]=1)=[N:9][NH:8][C:7]2=[O:22]
Reactant: COC1CCNCC1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3cccc(Cl)c23)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4cccc(Cl)c34)c2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 23.6 %

Procedure:
3-((8-chloro-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (118) (200 mg, 0.64 mmol) and 4-methoxypiperidine (73.2 mg, 0.64 mmol) were added to DMF (5 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.170 mL, 0.95 mmol) and then HBTU (362 mg, 0.95 mmol). The reaction mixture was stirred for four hours at 0° C. The crude mixture was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white crystalline solid (62.2 mg, 23.76% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.62-2.00 (3H, m), 3.02-3.29 (2H, m), 3.35 (3H, s), 3.37-3.65 (3H, m), 3.87-4.08 (1H, m), 4.69 (2H, s), 7.15-7.24 (3H, m), 7.29-7.34 (1H, m), 7.65 (1H, t), 7.77-7.81 (1H, m), 8.48 (1H, m), 9.85-10.01 (1H, m); m/z (LC-MS, ESI+), RT=1.80 (M+H 412.1).
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:31]([C:34]1[CH:35]=[C:36]([S:40]([NH2:43])(=[O:42])=[O:41])[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([C:7]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:43][S:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=4)(=[O:42])=[O:41])=[O:21])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A suspension of EXAMPLE 1D (39.8 mg, 0.05 mmol), 3-nitrobenzenesulfonamide (20.2 mg, 0.05 mmol), 4-dimethylaminopyridine (24.4 mg, 0.1 mmol) and 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (38.4 mg, 0.1 mmol) in dichloromethane (3 ml) was stirred for 16 hours at room temperature. The reaction mixture was concentrated and purified by RP HPLC (Zorbax SB-C8, gradient 30% to 100% CH3CN/water/0.1% TFA). 1H NMR (500 MHz, dimethylsulfoxide-d6) δ 10.49 (br s, 1H), 8.68 (s, 1H), 8.43-8.52 (m, 1H), 8.36 (d, 1H), 7.90 (t, 1H), 7.79 (d, 2H), 7.47 (t, 2H), 7.43 (t, 1H), 7.32-7.40 (m, 3H), 7.27 (d, 2H), 7.18 (d, 2H), 6.99 (d, 2H), 6.26 (t, 1H), 3.84 (d, 2H), 3.38-3.54 (br s, 4H), 3.32 (br s, 4H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2.[Cl:20]C1C=C2C(=CC=1)C=NC(O)=C2>>[Cl:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:5]2
Reactant: Oc1cc2cc(Cl)ccc2cn1
Reactant: O=S(=O)(Oc1cc2cc(F)ccc2cn1)C(F)(F)F
Product: O=S(=O)(Oc1cc2cc(Cl)ccc2cn1)C(F)(F)F

Procedure:
Following the procedure for trifluoromethanesulfonic acid 6-fluoroisoquinolin-3-yl ester, using 6-chloroisoquinolin-3-ol in place of 6-fluoroisoquinolin-3-ol, the title compound was obtained as a yellow solid. MS (ES+): m/z=311.69/313.63 [MH+]. HPLC: tR=3.88 min (ZQ2, polar—5 min).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[B]1OC2C(=CC=CC=2)[O:17]1>ClCCl.[Rh]>[C:10]1([C@@H:9]([OH:17])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [B]1Oc2ccccc2O1
Reactant: C=Cc1ccccc1
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A solution of rhodium-complex (3.4 mg, 4 μmol) obtained in Example 28 in dichloromethane degassed with argon was transferred with a syringe to the reaction vessel. Dichloromethane was evaporated in vacuo, then dry toluene (1 ml) degassed with argon, styrene (41.7 mg, 0.4 mmol) and freshly distilled catecholborane (56 μl, 0.45 mmol) were added. The reaction mixture was stirred at room temperature for 2 hrs, cooled with ice-bath, and quenched with EtOH (1 ml). 2M aqueous sodium hydroxide solution (1 ml) and 30% aqueous hydrogen peroxide (1 ml) were added. The mixture was allowed to warm up to room temperature over 30 min and then stirred for 2 hrs at this temperature. Diethyl ether (10 ml) was added to the mixture, and the orange organic layer was then washed with 1M aqueous sodium hydoxide solution and then dried over sodium sulfate. After evaporation of the solvent, the product was purified by chromatography on silica gel (pentane/diethyl ether 2:1) to give 35.7 mg of the title compound. (Yield: 73%, optical purity: 92% ee)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=1)=[O:9]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(Br)ccc1O
Yield: 50.3 %

Procedure:
Using 5-bromosalicylic acid and 3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH:18]=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1Cc2ccccc2N(Cc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1Cc2ccccc2N(Cc2ccccc2)C1

Procedure:
5.4 g of 1-benzyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline are reacted with 2.8 ml oxalyl chloride, 3.0 ml dimethylsulfoxide and 12 ml triethylamine analogously to Example 29b). Purification by means of FC is carried out over 500 g of silica gel (mobile phase D): Rf (D)=0.26; Rf (B)=0.41.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[OH:11][CH2:12][CH:13]([CH2:15]O)[OH:14]>>[OH:14][CH:13]1[CH2:12][O:11][CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[O:6][CH2:15]1
Reactant: COc1ccccc1C=O
Reactant: OCC(O)CO
Product: COc1ccccc1C1OCC(O)CO1

Procedure:
Using the method of Example 5e, 40.8 g 2-methoxybenzaldehyde and 27.6 g glycerol were reacted to form 5-hydroxy-2-(2-methoxyphenyl)-1,3-dioxane, crude b.p. 150°-155° C/10-5 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@H:19]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])[CH2:20][CH2:21][OH:22]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:14])([CH3:13])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:18][C@@H:19]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])[CH2:20][CH2:21][OH:22])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H](CCO)c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@](C)(F)C[C@H]1C(=O)N[C@H](CCO)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step A) from (2S,4R)-4-fluoro-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (prepared as described Scheme B18) and (R)-3-amino-3-(3-chloro-2-fluoro-phenyl)-propan-1-ol. TLC, Rf (EtOAc)=0.55; MS (UPLC/MS): 433.3 [M+H]+, 477.3 [M+HCOO]−; tR (HPLC conditions a): 3.26 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15]=3[C:14]3[C:13]4[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=4[CH:11]=[CH:10][C:9]2=3)=[CH:4][CH:3]=1.[C:29]1([C:35]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](B(O)O)=[C:41]3[C:36]=2[CH:37]=[CH:38][CH:39]=[CH:40]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(O)C>[C:29]1([C:35]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[C:9]5[CH:10]=[CH:11][C:12]6[CH:28]=[CH:27][CH:26]=[CH:25][C:13]=6[C:14]=5[C:15]5[C:16]6[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=6[CH:18]=[CH:19][C:20]4=5)=[CH:4][CH:3]=3)=[C:41]3[C:36]=2[CH:37]=[CH:38][CH:39]=[CH:40]3)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Reactant: Brc1ccc(-n2c3ccc4ccccc4c3c3c4ccccc4ccc32)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2c3ccccc3c(-c3ccc(-n4c5ccc6ccccc6c5c5c6ccccc6ccc54)cc3)c3ccccc23)cc1
Yield: 54.6 %

Procedure:
In a 200 mL three-neck flask were placed 1.7 g (4.0 mmol) of 7-(4-bromophenyl)-7H-dibenzo[c,g]carbazole and 1.2 g (4.0 mmol) of 10-phenylanthracene-9-boronic acid, and the air in the flask was replaced with nitrogen. To this mixture were added 15 mL of toluene, 5.0 mL of ethanol, and 4.0 mL of an aqueous solution of sodium carbonate. This mixture was degassed by being stirred while the pressure was reduced. To this mixture was added 0.23 g (0.20 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was stirred at 90° C. for 10 hours under a nitrogen stream, so that a solid was precipitated. The precipitated solid was removed by suction filtration. The collected solid was dissolved in about 50 mL of hot toluene, and this solution was suction-filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). A solid obtained by concentration of the filtrate was washed with toluene/hexane to give 1.3 g of a pale yellow powder, which was the object of the synthesis, in a yield of 55%. A synthesis scheme (d-2) of Step 4 is illustrated below.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1.Cl.C(OCC)C>CC(O)C>[ClH:1].[C:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][N:3]=2)=[CH:24][CH:25]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(NC(C)=O)cc2)ncc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 71.2 %

Procedure:
To a mixture of 2-[(2-chloro-5-nitropyrimidin-4-yl)amino]-N-methylbenzamide (54 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for 30 hours. After the reaction was cooled to room temperature the mixture was filtered, and the solid was washed with 2-propanol, hexane, and ethyl acetate. The solid was then dried under vacuum to give 2-[(2-{[4-(acetylamino)phenyl]amino}-5-nitropyrimidin-4-yl)amino]-N-methylbenzamide hydrochloride (58 mg, 71%) as a yellow tan solid. 1H NMR (DMSO-d6/D2O): δ 9.05 (s, 1H), 8.20 (m, 1H), 7.59 (d, 1 H), 7.40-7.50 (m, 5 H), 7.24 (t, 1 H), 2.76 (s, 3 H), 2.02 (s, 3H). MS m/z 421 (M+1).
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:27]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonamide (121 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (192 mg, 77%). MS (ISN) 497.0 [(M−H)−]; mp 210° C.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([NH:20][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: NC1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNC3CCC3)cc2)cc1
Reaction time: 48 h
Yield: 88.9 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.0 mmol) and cyclobutylamine (1.8 g, 25.0 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (1.57 g, 25.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 5.63 g (89%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.56-1.80 (m, 5H), 2.15-2.30 (m, 2H), 3.25-3.39 (m, 1H), 3.68 (s, 2H), 6.94-7.04 (m, 4H), 7.05-7.15 (tt, J=7.5, 1.5 Hz, 1H), 7.25-7.38 (m, 4H). MS (DCl/NH3) m/e 254 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:10][CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13].C1(C)C=CC=CC=1>Cl.C1(C)C=CC=CC=1.O>[CH3:19][C:17]1[C:11]([CH3:10])=[C:12]([OH:13])[C:6]2[C:4](=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][CH:7]=2)[N:5]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1ccccc1N
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc2c(O)c(C)c(C)nc12
Temperature: 200 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
12.3 g of 2-methoxyaniline, 14.2 g of ethyl 2-methylacetoacetate and 3 drops of 1N HCl are introduced into a 250 ml three-necked flask fitted with Dean-Stark apparatus and a condenser. The mixture is stirred overnight. 100 ml of toluene are added and the mixture is refluxed until distillation of the toluene/water azeotrope is complete. The toluene is then evaporated off and 100 ml of diphenyl ether are added. The mixture is heated at 200° C. for 1 h. 50 ml of diphenyl ether are evaporated off and the mixture is cooled to room temperature. 20 ml of petroleum ether are added and the product which crystallizes is filtered off. 2.1 g (yield: 10%) of 2,3-dimethyl-4-hydroxy-8-methoxyquinoline are obtained—m.p.: >290° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.O=S(Cl)Cl.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH:16]2[CH2:18][CH2:17]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: NC1CC1
Reactant: Cc1cc(Br)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-2-methylbenzoic acid and SOCl2 was refluxed for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 30 mL CH2Cl2 and combined with cyclopropyl amine (810.0 mg, 14.3 mmols) and pyridine,(2.05 g, 26.0 mmols). The solution was stirred for 18 hours and then diluted with EtOAc before being washed with 5% aqueous HCl, saturated NaHCO3, and saturated aqueous NaCl. The solution was dried (MgSO4) and concentrated under reduced pressure leaving the title compound as a colorless solid.
Reaction SMILES: [OH:1][C@H](CCCCC)CC(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=O.[OH:59][C@H:60]([CH2:112][CH2:113][C:114]1[CH:119]=[CH:118][CH:117]=[CH:116][CH:115]=1)[CH2:61][C:62](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:63]>>[OH:59][CH:60]([CH2:112][CH2:113][C:114]1[CH:119]=[CH:118][CH:117]=[CH:116][CH:115]=1)[CH2:61][C:62]([OH:63])=[O:1]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccccc1
Reactant: CCCCC[C@@H](O)CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Product: O=C(O)CC(O)CCc1ccccc1

Procedure:
The example 21 was reproduced except that (R)-3-hydroxyoctanoyl CoA was replaced by (R)-3-hydroxy-5-phenylvaleryl CoA (prepared by hydrolyzing 3-hydroxy-5-phenylvaleric acid ester obtained by a Reformatsky reaction to obtain 3-hydroxy-5-phenylvaleric acid and then by the method described in Eur. J. Biochem., 250, 432–439(1997)) to obtain colorant 10.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[CH:12]=[O:13].[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl>[Cl:14][CH2:15][C:16]([C:10]1[C:6]([CH3:5])=[C:7]([CH:12]=[O:13])[NH:8][C:9]=1[CH3:11])=[O:17]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c(C=O)c(C)c1C(=O)CCl
Reaction time: 0.25 h
Yield: 57 %

Procedure:
Anhydrous aluminum chloride (42 g, 315 mmol) was added portionwise over 30 min to a room temperature solution of 3,5-dimethylpyrrol-2-carboxaldehyde (5 g, 40 mmol) in 1,2-dichloroethane (50 ml) under nitrogen. After stirring for 15 min, chloroacetyl chloride (17 g, 150 mmol) was added dropwise over 1 h. After addition was complete, the mixture was stirred at room temperature for 16 h. The mixture was poured onto crushed ice and the organic layer separated, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. Yield 57%, m.p. 205–09° C. (toluene).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH:29]=O)[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35]>>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH2:29][NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1

Procedure:
Prepared according to Procedure D from 5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz, d6DMSO 9.51 (bs, 2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s, 2H), 4.14 (bs, 2H), 3.6-3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).