Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N:8]2[C:9](=[O:12])[C:10]=1[CH3:11].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C>[CH3:11][C:10]1[C:9](=[O:12])[N:8]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:7]2=[N:6][C:5]=1/[CH:4]=[CH:23]/[C:22]1[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=1
Reactant: Cc1nc2c(C)cccn2c(=O)c1C
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(/C=C/c2nc3c(C)cccn3c(=O)c2C)cc(OC)c1OC

Procedure:
To a solution of 1.3g of sodium methoxide in 75ml of absolute ethanol is added 2.0g of 2,3,9-trimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one, followed by 4.0g of 3,4,5-trimethoxybenzaldehyde. The mixture is stirred and heated under reflux for 89 hours. The reaction mixture is cooled, the solid is filtered, washed with 20ml of ether and 25ml of water, dried, and recrystallized from 75ml of acetonitrile to yield the title compound, melting point 218°-219°C dec.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C:5]([NH2:14])([CH2:10][CH2:11][CH2:12][NH2:13])[C:6](OC)=[O:7].C[O-].[Na+]>CO>[OH:3][CH2:4][C:5]1([NH2:14])[CH2:10][CH2:11][CH2:12][NH:13][C:6]1=[O:7]
Reactant: COC(=O)C(N)(CO)CCCN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC1(CO)CCCNC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.8 %

Procedure:
2-Hydroxymethyl-2,5-diaminopentanoic acid hydrochloride (5 g or 2.5×10-2 mol) is suspended in 75 ml of absolute methanol and the solution is saturated with dry hydrogen chloride. The homogenous solution is then heated under reflux for 48 hours. The reaction mixture is regularly saturated with dry hydrogen chloride. The solvent is evaporated under reduced pressure and the hygroscopic residue is dried under high vacuo (6.2 g) to give methyl 2-hydroxymethyl-2,5-diaminopentanoate dihydrochloride. The ester (6.2 g) is dissolved in 100 ml of absolute methanol, and 175 ml of a methanolic solution of sodium methylate (1.15 g of Na or 5×10-2 mol) is added. The reaction mixture is stirred at room temperature under nitrogen for 24 hours. The solvent is evaporated under reduced pressure and the residue is extracted many times with hot chloroform to yield analytically pure 3-hydroxymethyl-3-amino-2-piperidone (2.9 g): m.p. 145° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C@@H:29]1[C@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:32][C:31](=[O:40])[NH:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[C@H:29]([CH3:28])[C@H:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:32][C:31]3=[O:40])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)O[C@@H](c5ccccc5)[C@H]4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 12.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 9 and (4R,5S)-(+)-4-methyl-5-phenyloxazolidin-2-one (354 mg), the title compound (134 mg) was obtained.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:9][N:8]([C:4]2[CH:3]=[C:2]([CH3:10])[CH:7]=[CH:6][CH:5]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: Cc1cccc(NN)c1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(C)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of m-tolylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of a 50% pyridine in ethanol. The resulting oil was purified by flash chromatography to yield the named product as a solid (m.p. 46.5° C.-47.5° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCC3
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a solution of methyl [2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno [2,3-b]pyridin-3-yl]pentanoate (0.081 g; 0.199 mmol) in methanol (4 mL) and ethanol (2 mL) was added a 5% sodium hydroxide solution (5.3 mL; 6.625 mmol). The reaction mixture was heated under reflux for 4.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.038 g (50%) of the title compound as a white powder.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15](=[O:19])[CH2:16][CH:17]=[CH2:18]>>[OH:19][C@@H:15]([CH2:16][CH:17]=[CH2:18])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: C=CCC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C=CC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Is prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with 3-butenal.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21](/[CH:23]=[CH:24]/[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30][CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C>ClCCl>[O:32]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:30][CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
To a 25 mL of dry round bottom flask containing a solution of ethyl (2E)-3-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-ethylquinolin-4-yl]prop-2-enoate (300 mg, 0.67 mmol) in dichloromethane (5 mL) was added 2-nitrophenylsulfonylhydrazide (2.91 g, 13.4 mmol) followed by a solution of triethylamine (5 mL) in dichloromethane (10 mL) under nitrogen. The suspension was gently stirred for 6 hour at room temperature under nitrogen, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-40% ethyl acetate in petroleum ether) to afford 151 mg of the desired product (yield was 50%). MS obsd. (ESI+) [(M+H)+] 453.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:37][N:38]1[CH:42]=[N:41][N:40]=[CH:39]1>C(Cl)Cl>[N:41]1[N:40]=[CH:39][N:38]([NH:37][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][CH:9]=2)=[O:15])[CH:42]=1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: Nn1cnnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nn1cnnc1)c1cnc(-c2ccccc2)nc1
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid (300 mg, 1.5 mmol) in DCM (10 mL) is added 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide (316 mg, 1.65 mmol) and N-hydroxybenzotriazole (223 mg, 1.65 mmol) at rt and the mixture is stirred for 10 min. 4-Amino-4H-1,2,4-triazole (252 mg, 3 mmol) is added and the mixture is stirred at rt for 3 days. The resulting precipitate is filtered, washed with DCM and water, and dried in vacuum oven at 40° C. overnight to afford 2-phenyl-pyrimidine-5-carboxylic acid [1,2,4]triazol-4-ylamide (270 mg) as a solid. MS: 267 (M+H); 1H NMR (300 MHz, DMSO): δ=7.59 (m, 3H), 8.50 (d, 2H), 8.84 (s, 2H), 9.36 (s, 2H). IC50=262.5 nM.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19]O.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: OCCOC1CCCCO1
Reactant: O=C(O)c1cnc(Cl)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCOC1CCCCO1)c1cnc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (prepared as in Example 29, 3.15 g, 19.94 mmol) in methylene chloride (50 mL) was treated with 2-(tetrahydropyran-2-yloxy)ethanol (2.91 g, 19.94 mmol). The solution was cooled to 0° C. and then was treated with triethylamine (5.60 mL, 39.88 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (5.07 g, 19.94 mmol). The mixture was stirred at 0° C. for 15 min and then at 25° C. for 24 h. The mixture was extracted with methylene chloride and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded 5-chloro-pyrazine-2-carboxylic acid 2-(tetrahydro-pyran-2-yloxy)-ethyl ester as a colorless oil (3.41 g, 60%).
Reaction SMILES: CS(O[CH:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:7][CH3:8])(=O)=O.[Li+].[Br-:19]>CC(C)=O>[CH3:17][O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][CH:6]([Br:19])[CH2:7][CH3:8])[CH:11]=1
Reactant: [Br-]
Reactant: CCC(Cc1cccc(OC)c1)OS(C)(=O)=O
Agent: [Li+]
Solvent: CC(C)=O
Product: CCC(Br)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
To a solution of 1-{[3-(methyloxy)phenyl]methyl}propyl methanesulfonate (52) (4.66 g, 18.0 mmol) in acetone (60 mL) was added LiBr (3.13 g, 36.1 mmol). The reaction mixture was refluxed under nitrogen for 8 h. Another 0.80 g of LiBr was added, and the reflux was continued for 1 h. Cooled to room temperature, the solid was filtered off and washed with acetone. The filtrate was concentrated to give the crude product as a brown oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (100:1) to give 2.07 g (47%) of the title compound (53) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.06 (t, J=7.2 Hz, 3H), 1.70-1.82 (m, 1H), 1.83-1.95 (m, 1H), 3.10-3.20 (m, 2H), 3.80 (s, 3H), 4.10-4.20 (m, 1H), 6.75-6.85 (m, 3H), 7.22 (t, J=7.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([OH:13])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9]([O:13][C:21](=[O:23])[CH3:22])[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: CC(=O)Cl
Reactant: CON=C(C#N)C1=CCCN(O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON=C(C#N)C1=CCCN(OC(C)=O)C1
Temperature: 25 °C
Yield: 37.4 %

Procedure:
α-(Methoxyimino)-α-(1-hydroxy-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (E2) (0.5 g, 0.0028 moles) was dissolved in dry tetrahydrofuran (20 ml) and treated with triethylamine (0.43 ml, 0.0031 moles) with stirring at room temperature. This mixture was then treated with acetyl chloride (0.22 ml, 0.0031 moles) and stirred at ambient temperature for 2 h. The mixture was filtered and the filtrate evaporated to dryness. The residue was chromatographed on silica gel eluting with chloroform. The crystalline residue was recrystallised from 60-80 petrol to give the title compound (E10) as an off-white crystalline solid (0.234 g, 38%) m.p. 87°-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[H][H]>[Pt]=O.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Agent: O=[Pt]
Solvent: CCO
Product: Clc1cccc2c(C3CCNCC3)c[nH]c12

Procedure:
7-Chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (2.0 g, 8.62 mmol) and 0.5 g of platinum oxide were added to 100 mL of ethanol and the mixture was shaken under about 50 psi hydrogen at about ambient temperature for about a day. The mixture was filtered and the filtrate concentrated to yield a solid comprising the desired product. Yield 1.64 g (81%) as a yellow solid. FDMS m/e=234 (M+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:34][NH:35][C:36]1[N:41]=[C:40]([C:42]2[NH:43][C:44]3[C:49]([CH:50]=2)=[CH:48][C:47]([C:51]([OH:53])=O)=[CH:46][CH:45]=3)[CH:39]=[CH:38][N:37]=1.[CH3:54][O:55][C:56](=[O:73])[C@@H:57]([NH2:72])[CH2:58][N:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[N:65]=[CH:64][CH:63]=[CH:62][N:61]=1.C(=O)([O-])O.[Na+].C(OC(C)C)(=O)C>CN(C)C=O>[CH3:54][O:55][C:56](=[O:73])[C@@H:57]([NH:72][C:51]([C:47]1[CH:48]=[C:49]2[C:44](=[CH:45][CH:46]=1)[NH:43][C:42]([C:40]1[CH:39]=[CH:38][N:37]=[C:36]([NH:35][CH3:34])[N:41]=1)=[CH:50]2)=[O:53])[CH2:58][N:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[N:61]=[CH:62][CH:63]=[CH:64][N:65]=1
Reactant: CNc1nccc(-c2cc3cc(C(=O)O)ccc3[nH]2)n1
Reactant: COC(=O)[C@@H](N)CN(c1ccccc1)c1ncccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nccc(-c2cc3cc(C(=O)N[C@@H](CN(c4ccccc4)c4ncccn4)C(=O)OC)ccc3[nH]2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 51.1 %

Procedure:
4.01 g (10.6 mmol) of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)-uronium hexafluorophosphate and 6.82 g (52.8 mmol) of diisopropylethylamine were added to a solution of 2.36 g (8.80 mmol) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid in 80 ml of dimethylformamide under cooling with an ice bath, and the mixture was stirred at 0° C. for 1.5 h. Then a solution of 2.40 g (8.80 mmol) of (S)-2-amino-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester (98.9% ee (enantiomeric excess)) in 22 ml of dimethylformamide was added. The mixture was stirred for 2 h, and then an aqueous solution of sodium hydrogencarbonate and isopropyl acetate were added. The organic phase was separated, washed with a saturated solution of sodium chloride and concentrated in vacuo. The solid that precipitated was filtered off with suction, dried in vacuo and purified by column chromatography (silica gel, dichloromethane:methanol (25:1)). 2.35 g (50%) of (S)-2-{[2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carbonyl]amino}-3-(phenyl-pyrimidin-2-yl-amino)propionic acid methyl ester were obtained as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[N:6][CH:5]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl.CCN(CC)CC>CCOC(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[C:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[N:6][CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cncc(O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.31 g (2 mmol) of 5-hydroxy-nicotinic acid methyl ester, 0.73 g (4 mmol) of copper acetate, ˜1 g of 4 Å molecular sieves and 0.85 g (7 mmol) of phenylboronic acid were combined in a flask charged with 20 mL of DCM and 2.0 mL (14 mmol) of Et3N. This reaction slurry was stirred overnight at r.t. The reaction mixture was then diluted with 200 mL of EtOAc and washed 3 times with 10% K2CO3. The organic layer was then dried with Na2SO4, evaporated and purified by flash column chromatography (EtOAc/hexanes=1:2) to give 5-phenoxy-nicotinic acid methyl ester, which was subsequently hydrolyzed according to general procedure B to give 5-phenoxy-nicotinic acid and used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:18]=1[C:19]([N:21]=[C:22]=[O:23])=[O:20]>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:18]=1[C:19]([NH:21][C:22]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([S:9][C:10]([F:15])([F:14])[CH:11]([F:12])[F:13])=[CH:8][C:2]=1[F:1])=[O:23])=[O:20]
Reactant: Nc1ccc(SC(F)(F)C(F)F)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(SC(F)(F)C(F)F)cc1F
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
In 20 ml of toluene was dissolved 1.0 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylthio)aniline, and 0.8 g of 2,6-difluorobenzoyl isocyanate was added dropwise to the solution at room temperature (20° to 25° C.). After the reaction was allowed to proceed at the same temperature for 30 minutes, the crystals, which separated out, were recovered by filtration and washed with toluene to give 1.5 g of N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoro-ethylthio)phenyl]urea (Compound No. 1), m.p. of 177°-179° C.
Reaction SMILES: C(OC1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[OH:36])C2C(=CC=C(C)C=2)N(CCCC(C)C)C1=O)(=O)C1C=CC=CC=1.[C:37]([O:45][CH:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([Cl:55])[CH:53]=2)[N:48]([CH2:56][CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:47]1=[O:65])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:37]([O:45][C:46]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[OH:36])[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([Cl:55])[CH:53]=2)[N:48]([CH2:56][CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:47]1=[O:65])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c(O)c1
Reactant: O=C(OC1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21)c1ccccc1
Product: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCN3CCOCC3)c3ccc(Cl)cc32)c(O)c1

Procedure:
This compound was prepared in a similar manner to 3-(2-hydroxy-4-methoxybenzyl)-5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate by reacting 5-chloro-1-(3-morpholinopropyl)-2-oxoindolin-3-yl benzoate with tert-butyl (2-(hydroxymethyl)-5-methoxyphenyl)carbonate. 1H-NMR δ 8.02 (dd, 2H), 7.58 (dd, 1H), 7.45 (dd, 2H), 7.26 (m, 1H), 7.22 (d, 1H), 6.87 (d, 1H), 6.51 (d, 1H), 6.42 (d, 1H), 6.26 (dd, 1H), 3.73-3.70 (m, 8H), 3.62 (m, 1H), 3.54-3.50 (2H), 3.39 (d, 1H), 2.37-2.15 (m, 6H), 1.78 (m, 2H). Calculated mass for C30H31ClN2O6, 550.19. Observed 551.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4.25 g. of p-[[3,3-bis(p-chlorophenyl)propyl]amino]benzoic acid, ethyl ester, 2.85 g. of potassium hydroxide, and 50 ml. of 95% ethanol is heated at 75° C. for 26 hours, cooled, diluted with 150 ml. of water, and adjusted to pH 5 with 37% hydrochloric acid. The solid is collected, dried, and crystallized twice from isopropanol, giving 2.88 g. of the desired product as tan crystals, m.p. 213°-215° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14](OCC)[O:15]CC.O>C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[C:13][CH:14]=[O:15]
Reactant: CCOC(C#CCCCCCCCCCCCl)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=CC#CCCCCCCCCCCCl
Temperature: 62.5 °C
Yield: 87 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed 13-chloro-1,1-diethoxy-2-tridecyne (302.9 g: 1.0 mol), para-toluenesulfonic acid (8.0 g: 0.05 mol), water (170.0 g) and tetrahydrofuran (42.0 g), and then stirred at a reaction mixture temperature of from 60 to 65° C. During stirring, the pressure in the reactor was reduced gradually to 26.7 KPa to distill off refluxing ethanol. After stirring for 5 hours, completion of the reaction was confirmed by gas chromatography. The organic phase separated from the aqueous phase of the reaction mixture was washed with a solution of sodium chloride (5.0 g) in water (150.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, and then the residue was distilled under reduced pressure to obtain 13-chloro-2-tridecynal [bp: 116-122° C./0.13 KPa, 198.6 g, 0.87 mol]. [Yield: 86.8%]
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH2:14]([NH:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17].[O-2].[Mg+2]>C1COCC1.CCCCCC>[CH2:14]([N:18]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:2][CH:3]=[CH:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)CC(C)(C)CC=CCCl
Reactant: CCCCNCCCC
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCN(CC=CCC(C)(C)CC(C)(C)C)CCCC

Procedure:
10 g (49.5 mmol) of 1-chloro-5,5,7,7-tetramethyl-2-octene, 64 g (495 mmol) of di-n-butylamine and 10 g (248 mmol) of magnesium oxide in 30 ml of THF are refluxed for 4.5 h. The mixture is taken up in 200 ml of hexane, extracted twice with 5% strength methanolic NaOH and once with water and dried at 30° C./1 mbar. Yield: quantitative.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][C:34]2=[O:40])=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:26]([C:28]1[S:32][C:31]([N:33]2[CH:38]=[CH:37][C:36]([O:11][CH2:12][CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[CH:35][C:34]2=[O:40])=[N:30][C:29]=1[CH3:41])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCC3CCCC3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 57 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use cyclopentylmethyl 4-methylbenzenesulfonate in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 57% yield: mp 196-198° C. (methanol); 1H NMR (300 MHz, CDCl3) δ 8.64 (d, J=8.1 Hz, 1H), 7.40-7.25 (m, 5H), 6.16 (d, J=8.1, 2.6 Hz, 1H), 6.09-6.05 (m, 1H), 5.94 (d, J=2.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 3.83 (d, J=7.0 Hz, 2H), 2.68 (s, 3H) 2.41-2.27 (m, 1H), 1.87-1.77 (m, 4H), 1.66-1.58 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 167.9, 162.2, 162.1, 153.6, 152.2, 137.7, 131.3, 128.8, 127.9, 127.7, 122.1, 104.2, 96.6, 73.3, 44.1, 38.4, 29.3, 25.3, 17.3; MS (ES+) m/z 424.3 (M+1).