Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[N:8][O:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])#[N:2].C[O-].[Na+].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)O[C:21](=[O:22])C=2C=1.C(O)(=O)C>CO>[NH:2]=[C:1]([O:22][CH3:21])[C:3](=[N:8][O:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CCON=C(C#N)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCON=C(C(=N)OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-cyano-2-ethoxyiminoacetate (syn isomer) (4.7 g) in methanol (50 ml) was added 1 N methanolic solution (5 ml) of sodium methoxide under cooling in an ice-bath and stirring, which was continued for 20 minutes in an ice-bath and 15 minutes at room temperature. The mixture was neutralized to the end point of phenolphthalein with 1 N methanolic solution of acetic acid and evaporated. The residue was dissolved in methylene chloride (80 ml), washed with water, dried over magnesium sulfate and evaporated to give methyl 3-imino-3-methoxy-2-ethoxyiminopropionate (syn isomer) (4.8 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:11](=[O:27])[C:10]=2[C:28]([OH:30])=O)=[CH:5][CH:4]=1.[NH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[N:13][N:12]([CH2:23][CH:24]3[CH2:25][CH2:26]3)[C:11](=[O:27])[C:10]=2[C:28](=[O:30])[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: NCc1ccccn1
Product: COc1ccc(-c2nn(CC3CC3)c(=O)c(C(=O)NCc3ccccn3)c2-c2ccc(OC)cc2)cc1

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-carboxy-2-cyclopropylmethyl-2H-pyridazin-3-one and 2-(aminomethyl)pyridine as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained quantitatively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C#CCCCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Product: CCCCCCCCCCCC#Cc1cccc(C=O)c1
Yield: 85 %

Procedure:
Reaction of 3-bromobenzaldehyde with 1-tridecyne as described in example 3 gave 85% of the title compound after chromatography on silica, eluting with dichloromethane:petrol (bp 40:60) (1:3) νmax (neat) 2920, 2215, 1705, 1600, 1575, 1465, 1280, 1155, 795, and 680 cm-1, δ(CDCl3) 0.86 (3H, distorted t), 0.9-1.7 (18H, m), 2.4(2H, t, J=6 Hz), 7.7-7.9 (4H, m, aromatic), and 10.0 (1H, s, aldehyde). Analysed as the 2,4-dinitrophenylhydrazone m.p. 127° C. (recrystallized from acetic acid). Found, C, 67.27, H, 6.86; N, 12.01, C26H32N4O4 requires, C, 67.33, H, 6.79, N, 12.08%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1>CN(C=O)C.C1COCC1.[Pd]>[N:10]1[C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.5 %

Procedure:
A mixture of 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (1 mmol) and Pd/C (20 mg) in DMF/THF (10 ml/10 ml) was stirred at r.t. for 6 h equipped with a H2 balloon. Then the solvent was removed under reduced pressure and 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile was obtained with a yield of 88.5%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:34]O)[CH2:10][C:11]1[CH:33]=[CH:32][C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS([Cl:47])(=O)=O.[Cl-].[Li+]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:47][CH2:34][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][C:11]1[CH:33]=[CH:32][C:14]([O:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](CCl)Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reaction time: 4 h

Procedure:
5.5 g (11.3 mmol) of benzyl 4-[4-[(2S)-2-(t-butoxycarbonylamino)-3-hydroxypropyl]phenoxy]piperidine-1-carboxylate was dissolved in 60 ml of dichloromethane. 3.2 ml (22.6 mmol) of triethylamine and 1.95 g (17.0 mmol) of methanesulfonyl chloride were added to the solution. After stirring for 4 hours, the reaction mixture was treated by the isolation process with dichloromethane as the extractant in the same manner as that of step 1 in Example 1 to obtain an oily residue, which was dissolved in 120 ml of dimethylformamide. 2.57 g (60.6 mmol) of lithium chloride was added to the solution, and they were stirred at 50° C. for 15 hours. After the isolation process with ethyl acetate as the extractant in the same manner as that of step 1 in Example 1, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([C:23]([CH3:28])([CH3:27])[CH2:24][CH:25]=O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:25]/[CH2:24][C:23]([C:20]1[CH2:21][CH2:22][N:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH:19]=1)([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(CC=O)C1=CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1=CCN(Cc2ccccc2)CC1
Yield: 101.2 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.84 g, 6.4 mmol) was reacted with 3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-butyraldehyde (1.65 g, 6.4 mmol) in CH2Cl2 at room temperature for 5 h to give [3-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (2.4 g, 100%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH:4]([CH3:6])[CH3:5].[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]=[O:24]>>[CH3:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:22]=[C:23]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C@@H:3]([CH:4]([CH3:6])[CH3:5])[CH2:2][O:24]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: CC(C)CN[C@H](CCl)C(C)C
Product: Cc1cc([N+](=O)[O-])ccc1N=C1OC[C@H](C(C)C)N1CC(C)C

Procedure:
(L)-Valine methyl ester was reduced to (1S)-1-(hydroxymethyl)-2-methylpropylamine according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford (4S)-2,4diisopropyl-1,3-oxazolidine. The oxazolidine was reduced according to Method B4c, Step 2 to give (1S)-1-(hydroxymethyl)-N-isobutyl-2-methylpropylamine. The substituted 2-hydroxyethylamine was reacted with SOCl2 according to Method B7b to give (1S)-1-(chloromethyl)-N-isobutyl-2-methylpropylamine. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isocyanate according to Method C4a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-isopropyl-1,3-oxazolidine.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1.C(=O)=O>CO>[CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19]4[CH:20]=[N:21][CH:22]=[N:23][CH:24]=4)=[CH:12][CH:13]=3)[C@:8]3([CH2:28][O:27][C:26]([NH2:29])=[N:25]3)[C:7]=2[CH:6]=1
Reactant: CC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: O=C=O
Solvent: CO
Product: CC(C)(C)C#Cc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Yield: 41.6 %

Procedure:
Racemic 2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (490 mg) was subjected to chromatography using 20:80:0.1 MeOH:CO2:DEA at 65 ml/min on a 20×150 mm ChiralPak AD-H column and 100-bar system pressure. The first peak (RT=3.51 min) provided (4S)-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (204 mg, 99% ee), and the second peak (RT=5.44 min) provided (4R)-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (>99% ee).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](Br)[CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][O:23]3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: BrCC1CCCO1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(OCC3CCCO3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with tetrahydro-furfuryl bromide, whereby the product was isolated as free base, (rac) 2-methyl-4-pyrrolidin-1-yl-7-(tetrahydro-furan-2-ylmethoxy)-quinoline as a yellow-brown waxy solid. ISP mass spectrum, m/e: 313.2 (M+1 calculated for C19H24N2O2: 313).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][C:17]([OH:23])=[CH:16][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][C:17]([O:23][CH2:37][CH:39]1[O:41][CH2:40]1)=[CH:16][CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccc(O)cc12
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccc(OCC3CO3)cc12

Procedure:
Reaction of 3′,4′-dibenzyloxy-6-hydroxy-flavone, 24 (4.5 g, 10 mmol), 50% sodium hydride (1.4 g, 60 mmol) and epichlorohydrin (4.7 mL, 60 mmol) in dry dimethyl formamide (120 mL) using identical procedure as described for 28 furnished 30. Yield 4.2 g (81%); mp 147-149° C.; MS (FAB) 507 (M++1); IR (KBr) 1610; 1H NMR (200 MHz, CDCl3) δ 7.57-7.29 (m, 15H), 7.02 (d, J=8.6 Hz, 1H), 6.66 (s, 1H), 5.25 (s, 4H), 4.39 (dd, J=11.0 Hz, 2.6 Hz, 11H), 3.98 (dd, J=11.0 Hz, 6.0 Hz, 1H), 3.40-3.39 (m, 1H), 2.93 (t, J=4.5 Hz, 4.5 Hz 1H), 2.78 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([O:17]CC)[CH3:16].C(OC(=O)C)(=O)C>CCCCCC>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)(=[O:17])[CH3:16]
Reactant: CCOCC
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C=Cc1ccc(NC(C)=O)cc1

Procedure:
A sample of 50 g. of ethyl p-aminocinnamate is dissolved in 500 ml. of ethyl ether and a solution of 28 g. of acetic anhydride in 30 ml. of ether is added dropwise. When the addition is complete, the reaction is allowed to stir for another hour. The mixture is then diluted with hexane and filtered, providing ethyl p-acetamidocinnamate.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]1[C:9](=[O:10])[N:8](/[CH:11]=[CH:12]/[C:13]([F:16])([F:15])[F:14])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:6]1.[OH-].[Li+].Cl>CO.CS(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:8](/[CH:11]=[CH:12]/[C:13]([F:15])([F:14])[F:16])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:24])=[O:2])[N:6]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
260 mg (0.72 mmol) of the compound of Example 10A were dissolved in 5 ml of methanol, and 2.87 ml (2.87 mmol) of a 1M aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 1 h and then acidified with 1N hydrochloric acid and diluted with DMSO. The entire solution was purified by preparative HLPC [Method 9]. This gave 215 mg (86% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=[C:12]([O:14]C)[CH:13]=2)=[C:6]([NH:20][C@H:21]([C:23]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:27](=[O:35])[C:26]3=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]3[N:24]=2)[CH3:22])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([NH:16][C:17]([NH2:19])=[O:18])[CH:11]=[C:12]([OH:14])[CH:13]=2)=[C:6]([NH:20][C@H:21]([C:23]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:27](=[O:35])[C:26]3=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]3[N:24]=2)[CH3:22])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(NC(N)=O)cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(NC(N)=O)c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
(S)-1-(3-(4-Amino-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidin-5-yl)-5-methoxyphenyl)urea (50 mg, 0.10 mmol) was dissolved in dichloromethane (1.5 ml). A solution of boron tribromide (1M in dichloromethane, 285 μl, 0.29 mmol) was added dropwise and the reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 27 mg (55% yield) of the title compound. Purity 100%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:6]=[C:5]2[C:19]([O:21][CH3:22])=[O:20].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:19]([O:21][CH3:22])=[O:20])=[CH:6][N:7]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:3][C:2]=1[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2cc(Cl)c(-c3ccc(O)cc3)cc12
Temperature: 85 °C
Yield: 89 %

Procedure:
A mixture of 1-tert-butyl 3-methyl 5-bromo-6-chloro-1H-indole-1,3-dicarboxylate (300 mg, 0.78 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (255 mg, 1.16 mmol), 1,4-dioxane (4.2 mL) and aqueous potassium phosphate tribasic (4.6 mL, 0.5 M, 2.3 mmol) was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.78 mmol). The pink mixture was evacuated and refilled with nitrogen three times. The sealed reaction was heated at 85° C. for 10 minutes. The cooled reaction mixture was filtered through Celite, and the filter pad was washed with water followed by three washes with ethyl acetate. The filtrate layers were separated, and the aqueous layer was extracted again with ethyl acetate. The organic extracts were combined, washed with brine and then dried over sodium sulfate. The mixture was filtered and concentrated in vacuo to give an oily solid which was purified by flash chromatography eluting with heptanes/ethyl acetate (90:10 to 40:60) to give the title compound (279 mg, 89% yield) as a white solid. MS (ES+) 302 (M-Boc+1)+. 1H NMR (500 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.26 (d, J=8.29 Hz, 2H), 6.86 (d, J=8.54 Hz, 2H), 3.32 (s, 3H), 1.66 (s, 9H).
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1.[CH2:29]([OH:32])[CH2:30][OH:31].[OH-].[K+].O>ClCCl>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[OH:31][CH2:30][CH2:29][O:32][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:28]=2[S:27][C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[SH+:20]3)=[CH:11][CH:10]=1
Reactant: OCCO
Reactant: Fc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCCOc1ccc(-c2cccc3c2Sc2ccccc2[SH+]3)cc1
Temperature: 120 °C
Yield: 91.6 %

Procedure:
A round bottom flask was charged with 0.2 g (0.438 mmol) of 9-(4-fluoro-phenyl)-thianthrenium hexafluorophosphate, and 5.0 g of ethylene glycol. The mixture was heated up to 120° C. and stirred until complete dissolution. 50 mg of potassium hydroxide were added to this solution; the solution was stirred for 1 hour and then poured into water. Dichloromethane was added and the organic layer separated, washed with water and dried (Na2SO4). After drying the solvent was removed under vacuum to give a white solid (0.2 g, 92%).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:9]([O: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][CH2:25][CH2:26][CH2:27][CH3:28])[C@@H:8]([CH2:29][O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:7][C@H:4]1[O:5][CH3:6].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C@@H:3]1[C@@H:9]([O: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][CH2:25][CH2:26][CH2:27][CH3:28])[C@@H:8]([CH2:29][OH:30])[O:7][C@H:4]1[O:5][CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@@H](OC)[C@H](OC)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@@H](OC)[C@H](OC)O[C@@H]1CO
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
To a solution of methyl 2-O-methyl-3-O-octadecyl-5-O-trityl-β-D-xylofuranoside (3.2 g) in dry methylene chloride (32 ml) was added trifluoroacetic acid (3.2 ml) in one portion at ambient temperature. After stirring for 1.5 hours at the same temperature, the yellow solution was washed with water, aqueous sodium bicarbonate and water succesively, dried, and evaporated under reduced pressure. The residue was triturated in n-hexane to remove triphenylcarbinol by filtration. The filtrate was evaporated and then the residue was purified by column chromatography on silica gel (40 g, elution by chloroform) to yield 1.21 g of methyl 2-O-methyl-3-O-octadecyl-β-D-xylofuranoside as a thick oil.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(O)C>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: NCCCO
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc2nc(NCCCO)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 38, reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.45 g) and 3-amino-1-propanol (0.98 g) in ethanol (15 ml) yielded the title compound, 0.31 g, m.p. 185-6° C. (recrystallized from ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([CH:6]([C:11]#[N:12])[C:7](OC)=[O:8])=[O:5].C[O-].[Na+]>N1C=CC=CC=1>[C:11]([C:6]1[C:7]([OH:8])=[N:1][C:2]2[C:3]([C:4]=1[OH:5])=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)#[N:12]
Reactant: COC(=O)C(C#N)C(=O)c1cc([N+](=O)[O-])ccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1c(O)nc2ccc([N+](=O)[O-])cc2c1O

Procedure:
A 13.16 g portion of the methyl 2-(2'-amino-5'-nitrobenzoyl)cyanoacetate, produced as described in Example 4 (molecular weight 263) was cyclized by refluxing for 8 hours with 2.81 g sodium methoxide (molecular weight 54) in 60 ml pyridine. After cyclization the pyridine was distilled and the batch was worked up as described above in Example 3. That part of the reaction product which was water insoluble before the acidification was not the desired quinoline derivative and was discarded. The precipitate which formed after acidification of the clear yellowish-brown mother liquor to pH 2.5 was found by infrared spectroscopy and nuclear magnetic resonance to be the crude desired product (melting point 281°-282° C.). The yield was 7.5 g, 64.9 percent of theory based on starting methyl ester of 2-(2'-amino-5'-nitrobenzoyl) cyanoacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]=[C:10]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:11]2=[O:13]
Reactant: CCOC(=O)C(C=Nc1ccc(Br)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=c1c(-c2ccccc2)c[nH]c2ccc(Br)cc12
Temperature: 150 °C

Procedure:
A mixture of ethyl 3-((4-bromophenyl)imino)-2-phenylpropanoate (6.18 g, 17.8 mmol, Intermediate 3, step a) and polyphosphoric acid (8.90 g) was heated at 150° C. for 1.5 hours. After cooling to room temperature, 3 N NaOH was added at 4° C. until basic. The solid was filtered, washed with water, and dried under vacuum overnight to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]([C:11]([CH3:13])=O)[C:6]([O:8]CC)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23].CS(O)(=O)=O.O>C1(C)C(C)=CC=CC=1>[CH3:28][O:27][C:25]1[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[C:22]2[C:24]=1[C:11]([CH3:13])=[C:5]([CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[F:1])[C:6](=[O:8])[NH:23]2
Reactant: CCOC(=O)C(Cc1ccccc1F)C(C)=O
Reactant: COc1cc(N)cc(OC)c1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cc(OC)c2c(C)c(Cc3ccccc3F)c(=O)[nH]c2c1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(2-fluorobenzyl)acetoacetate (2.5 g) in xylene (1 ml) was heated to 150° C. and 3,5-dimethoxyaniline (1.46 g) in xylene (4 ml) was added in small portions during 30 minutes. The reaction mixture was heated at 160° C. for 3 hours and then cooled to room temperature. Methanesulfonic acid (1.7 ml) was added and the mixture was stirred at ambient temperature for 30 minutes. Water was added and the precipitate filtered and dried. The product was triturated with warm ethanol. Yield 0.64 g (21%).
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][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:27]([CH3:33])=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1>C(OCCO)C>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])=[C:27]([CH3:33])[CH:28]=1
Reactant: Cc1cc(O)ccc1N
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3C)c2cc1OC
Yield: 90.8 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 4-amino-m-cresol to give 304.6 mg (90.9%) of the product as a salmon solid, m.p.>250° C., mass (electrospray, m/e): M+H 335.9