Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14]([Br:16])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)C1C=CC=CC=1.[OH-].[Na+].Cl>CO>[CH2:26]([O:25][C:11]1[CH:12]=[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([Br:16])=[CH:15][C:10]=1[C:9]([OH:33])=[O:8])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 75 %

Procedure:
A flask was charged with benzyl-2,4-bis-benzyloxy-5-bromobenzoate (25 g; 50 mmol); 5N aqueous sodium hydroxide (80 mL), and methanol (200 mL). The reaction was heated at reflux overnight, cooled, and acidified to pH=2 with concentrated hydrochloric acid. The solvent was reduced by half using evaporation, and the solid was filtered, washed with water (100 mL), dissolved in dichloromethane, dried with sodium sulfate, and evaporated to give 2,4-bis-benzyloxy-5-bromobenzoic acid (15.5 g; 37.5 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]([OH:20])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:23]=1[NH2:24].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18](=[O:20])[NH:24][C:23]1[C:22]([F:21])=[CH:28][CH:27]=[CH:26][C:25]=1[F:29])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To the solution of (S)-3,4-dihydro-1H-isoquinoline-1,2-dicarboxylic acid 2-tert-butyl ester (500 mg, 1.8 mmol, Eq: 1.00) and 2,6-difluoroaniline (279 mg, 2.16 mmol, Eq: 1.2) in pyridine (10.0 mL) at 0° C. was added POCl3 (415 mg, 252 μL, 2.7 mmol, Eq: 1.5). The mixture was warmed to RT and stirred for 2 h. The solvent was evaporated, water was added and the mixture extracted with EtOAc. The combined organics were washed with water, brine, dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography to give (S)-1-(2,6-difluoro-phenylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (380 mg) as a white foam.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24]Br>>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Br:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: BrCc1cc(Br)cc(Br)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(Br)cc(Br)c2)c(=O)[nH]c1=O
Yield: 67.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dibromobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (356 mg, yield: 67.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][Cl:22])=[N:19][N:18]=[C:17]2[CH2:23][NH:24][C:25]([O:27]CC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].Br.[C:36](O)(=O)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][Cl:22])=[N:19][N:18]=[C:17]2[CH2:23][NH:24][C:25](=[O:27])[CH3:36])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1)OCc1ccccc1
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 5-chloro-2-[3-(N-carbobenzoxyaminomethyl)-5-chloromethyl-4H-1,2,4-triazol-4-yl]-benzophenone (0.995 g) and 30% hydrogen bromide-acetic acid (2 ml) is stirred at room temperature for 1.25 hours, and the mixture is washed with ether (50 ml) twice. The obtained free base is mixed with benzene (10 ml), acetyl chloride (0.5 g) and dimethylformamide (6 ml), and the resultant mixture is stirred at room temperature for 2 hours, and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate, and the precipitated crystals are filtered and washed with ether and chloroform in order to give 5-chloro-2-(3-acetamidomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl)-benzophenone (0.6 g) as crystals melting at 193° to 199° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[CH2:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]1[OH:19].N12CCCN=C1CCCCC2.Cl[Si:32]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[O:33][Si:34](Cl)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36]>C(C#N)(C)=O>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:12]([OH:19])[C@@H:13]2[O:18][Si:32]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[O:33][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:36])[CH3:37])[O:17][CH2:16][C@H:14]2[CH2:15]1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Reactant: OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Agent: CC(=O)C#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-(6-chloro-purin-9-yl)-5-hydroxymethylcyclopentane-1,2-diol (Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075-308) (0.44 g, 1.55 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.461 mL, 3.1 mmol) in AcCN (15 mL) was added 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (0.581 mL, 1.8 mmol). The reaction mixture was stirred at room temperature for 14 h then concentrated. The residue was purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.545 g, 67%)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCOCC1>[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]1[O:19][C:11]2[C:10](=[O:13])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:14])[C:2]=2[N:1]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccccc3Cl)nc21
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
To a solution of 5 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 60 mL of dioxane, 15.3 mL (120 mmol) of 2-chlorobenzoic acid chloride are added; after 5 min of stirring, 0.5 mL of concentrated sulfuric is added. The reaction mixture is heated to reflux for 4 h, and the precipitate obtained after evaporation of the dioxane at a reduced pressure is dissolved in 200 mL of dichloromethane. To this solution, 100 mL of a cold 10N sodium hydroxide solution are added. The mixture is stirred for 2 h. The organic phase is then extracted, washed several times with water and dried over calcium chloride. The solid residue obtained after evaporation of the solvent is purified on a medium-pressure column (support: silica; eluant: dichloromethane/heptane, 40/60). The product obtained is recrystallized after color removal in a heptane/dichloromethane mixture (1/1) to produce 5 g of 2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole in the form of light yellow crystals.
Reaction SMILES: Cl.[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:6].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:2]([O:18][CH3:19])(=[O:17])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][C:9]([N:10]1[CH2:15][CH2:14][N:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1)=[O:16])=[O:6]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
Methyl 2-oxo-2-piperazinylethyl(2E)but-2-ene-1,4-dioate hydrochloride (14) (0.50 g, 1.71 mmol) was reacted at ca. 0° C. with benzyl bromide (BnBr) (0.243 mL, 0.35 g, 2.05 mmol) and diisopropylethylamine (DIEA) (1.00 mL, 0.74 g, 5.76 mmol) in dichloromethane (DCM) followed by warming to room temperature. After aqueous work-up, the crude product was purified by mass-guided preparative HPLC to afford 0.18 g (27% yield) of the title compound (15) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.08-7.01 (m, 5H), 6.72-6.71 (m, 2H), 4.60 (s, 2H), 3.58-3.57 (s, 3H), 3.23-3.19 (br S, 2H), 3.30 (s, 2H), 3.1.19-3.11 (br S, 2H), 2.23 (br S, 4H); MS (ESI) m/z 347.13 (M+H)+.
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].I[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:20]/[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27])/[C:13](=[O:19])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][NH:22][C:21]=1/[CH:20]=[C:12]1\[C:13](=[O:19])[NH:14][C:15]2[C:11]\1=[C:10]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:8])=[O:7])[CH:18]=[CH:17][CH:16]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CCCCC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCC(N)=O)c21

Procedure:
Using Method C above, 5-hexynamide (46 mg, 0.4 mmol) (prepared from 5-hexynoic acid by Method G above) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (113 mg, 0.31 mmol) using (Ph3P)2PdCl2 (12 mg) and CuI (6 mg) as catalyst in DMF (1 mL) and Et3N (1 mL) as solvent at 70° C. for 22 h yielding (Z)-6-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-5-hexynamide. (Yield 52 mg, 48%).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)[C:9]1=[O:24])[C:4]([O:6]C)=[O:5].[Li+].[OH-]>O1CCCC1.O>[CH3:1][C:2]([CH3:26])([CH3:25])[C@H:3]([N:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[N:15]=2)[C:9]1=[O:24])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](N1CCN(Cc2nc3ccccc3n2C)C1=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product of Example 64E (37 mg) in tetrahydrofuran (0.26 mL) and water (0.13 mL) was treated with LiOH (6.1 mg, 1.4 equivalents), stirred at 25° C. for 16 hours, quenched with 1N HCl (0.15 mL) at 0° C., and the solvents were evaporated to give the title compound, to be used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1.[Cl:10][CH:11]([Cl:19])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1>>[Cl:10][CH:11]([Cl:19])[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[N:7][CH:8]=1
Reactant: ClCc1ccc(Cl)nc1
Agent: Clc1ccc(C(Cl)Cl)cn1
Product: Cc1ccc(Cl)nc1

Procedure:
The present invention relates to the preparation of 5-aminomethyl-2-chloropyridines by reacting a mixture of 5-chloromethyl-2-chloropyridine and 5-dichloromethyl-2-chloropyridine with substituted amines. The mixture of 5-chloromethyl-2-chloropyridine and 5-dichloromethyl-2-chloropyridine is obtained by chlorination of the 5-methyl-2-chloropyridine.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:7][C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13](I)=[N:12][N:11]3[CH:17]=2)=[O:6])[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]([OH:26])[CH:22]=[CH:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[CH3:25])[O:26][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:17]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:9]=2)[N:12]=1
Reactant: O=C(CC1CC1)Nc1cn2nc(I)ccc2n1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CC4CC4)cn3n2)cc1N
Yield: 46.6 %

Procedure:
Using 2-cyclopropyl-N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (300 mg, 0.877 mmol), 3-amino-4-methylphenol (216 mg, 1.754 mmol), potassium carbonate (182 mg, 1.316 mmol) and N,N-dimethylformamide (3 mL), and by a reaction in the same manner as in Example 191, the title compound (138 mg, 47%) was obtained as a orange powder.
Reaction SMILES: [OH-].[Na+].[C:3]12([C:13](=[O:17])[C:14]([OH:16])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[Mn]([O-])(=O)(=O)=[O:19].[K+]>O>[OH:19][C:9]12[CH2:11][CH:5]3[CH2:6][CH:7]([CH2:12][C:3]([C:13](=[O:17])[C:14]([OH:16])=[O:15])([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C(O)C(=O)C12CC3CC(CC(C3)C1)C2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 55 °C
Reaction time: 9 h

Procedure:
2.8 mL of NaOH 30% solution in water was diluted with 30 mL of water. The solution was heated to 55° C. and 3.0 g of adamantaneglyoxylic acid was dissolved therein. Then 3.3 g of potassium permanganate was added gradually during 2 h and stirring of obtained the obtained mixture was continued for 9 h at 55–60° C. The mixture was allowed to stay at room temperature for overnight. Then manganese dioxide precipitate was filtered out and the filtrate work-up procedure consisting of acidification, extraction with organic solvent and concentration of the combined organic phases resulted in 2.5 g of the target 3-hydroxyadamantaneglyoxylic acid (1) with purity 68.9% according to GC analysis of the corresponding methyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[NH:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[NH:11][CH:12]=[C:13]([CH3:15])[N:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Cc2nc(C)c[nH]2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1c[nH]c(Cc2ccc(O)cc2)n1
Reaction time: 17 h
Yield: 90.7 %

Procedure:
A mixture of 2-(p-methoxyphenylmethyl)-4-methylimidazole (5.0 g, 0.025 m), glacial acetic acid (37 mL) and 48% hydrobromic acid (125 ml) was heated at reflux for 5 hours. The solution was concentrated under reduced pressure and the oily residue was stirred in saturated sodium bicarbonate solution (55 mL) for 17 hours. The solid was collected and dried to yield 4.22 g (90%) of II; m.p. 193°-194° C. (CH3CN).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.FC(F)(F)O[C:39]1C=C(S(Cl)(=O)=O)C=C[CH:44]=1>>[CH2:39]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][N:13]3[S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:34])[F:35])[CH:5]=3)(=[O:11])=[O:12])=[CH:17][CH:18]=2)=[O:23])=[CH:26][CH:27]=1)[CH3:44]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)(F)F)c2)CC3)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(OC(F)(F)F)c2)CC3)cc1

Procedure:
4-{[1-(3-Trifluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=505.1 (M−H), was prepared in analogy to example 30, steps 1 to 6. Step 5 was performed using 3-trifluoromethoxy-benzenesulfonyl chloride, yielding 4-{[1-(3-trifluoromethoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1Br.[C:25]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1[C:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Reactant: OB(O)C1=CCCCCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(N)c(C3=CCCCCC3)c2)CN(C)C1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A solution of 5-(4-amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one trifluoroacetic acid salt (as prepared in Example 7, step (b), 105 mg, 0.352 mmol), cycloheptene-1-yl boronic acid (74 mg, 0.52 mmol), K3PO4 (224 mg, 1.05 mmol), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3) (32 mg, 0.034 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (57.5 mg, 0.350 mmol) in toluene (0.7 mL) was heated at 100° C. under Ar for 1 h. The reaction mixture was allowed to cool to RT and filtered. The filter cake was washed with DCM (2×10 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc-hexane) to afford the title compound (95 mg, 86%): Mass spectrum (ESI, m/z): Calcd. for C19H27N3O, 314.2 (M+H). found 314.3.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[C:4](O)=[O:5].B.O>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([CH3:14])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Temperature: 75 °C
Yield: 93.8 %

Procedure:
2,6-Dimethyl-3-nitrobenzoic acid (10 g) was dissolved in 100 ml of dry tetrahydrofuran and 165 ml of 1 M borane in tetrahydrofuran added. The mixture was heated to 75° C. for 4 hr. The mixture was cooled to room temperature and the excess reagent slowly decomposed with water and the solvent evaporated. The residue was treated with ethyl acetate, washed with 1M hydrochloric acid, then with water, dried, and evaporated to give 8.71 g of (2,6-dimethyl-3-nitro-phenyl)-methanol, mp 94.5-96.1° C. ##STR142##
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[Li]CCCC.[Br:25]Br>C1CCCCC1>[Br:25][C:9]1[S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][C:10]=1[C:12]([OH:14])=[O:13]
Reactant: BrBr
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)sc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-phenyl-1,3-thiazole-4-carboxylic acid (3.2 g) in abs. THF (190 mL) was added at 78° C. over 10 min n-BuLi (25 mL, 1.6M in hexanes). After addition, Br2 (1.3 mL) in cyclohexane (7.4 mL) was added over 10 min. The reaction mixture was allowed to warm up to RT and was stirred at this temperature for 3 h. The reaction mixture was then cooled to 0° C., carefully quenched with HCl (1M, 32 mL) and extracted with EtOAc (2×). The combined org. phases were washed with aq. sodium thiosulfate (20%), dried over MgSO4 and evaporated to dryness to give 4.5 g of the desired product. The crude was used without further purification.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([N:13]1[C:18]([NH:19][NH:20][C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=S)=[CH:17][C:16](=[O:30])[N:15]([CH2:31][CH2:32][CH3:33])[C:14]1=[O:34])[CH2:10][CH2:11][CH3:12].CCCCCC>C(Cl)(Cl)Cl>[CH2:9]([N:13]1[C:18]2[NH:19][N:20]=[C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=2[C:16](=[O:30])[N:15]([CH2:31][CH2:32][CH3:33])[C:14]1=[O:34])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(NNC(=S)NCC(=O)OCC)cc(=O)n(CCC)c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(NCC(=O)OCC)n[nH]c21
Reaction time: 1 h

Procedure:
To a stirred suspension of N-chlorosuccinimide (6.5 g) in chloroform (80 ml) was added in portions 1-butyl-6-(4-ethoxycarbonylmethylthiosemicarbazido)-3-propylpyrimidine-2,4(1H,3H)-dione (18 g) under ice-cooling. The mixture was stirred for one hour, followed by addition of hexane (200 ml) to give an insoluble product. The insoluble product was filtered off.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=2)=[CH:46][C:45]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][CH:62]=1.CCOCC>ClCCl.Cl>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH:50][C:51](=[O:60])[C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([O:58][CH3:59])[CH:53]=2)=[CH:46][C:45]=1[C:61]1[N:65]([CH3:66])[N:64]=[CH:63][CH:62]=1)=[O:5]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)CN(C)C)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
2-(dimethylamino)acetic acid (16.0 mg, 1.25 eq), triethylamine (34.6 mL, 2.0 eq) and HATU (59.0 mg, 1.25 eq) were dissolved in 3 mL of dichloromethane and stirred at room temperature for 10 minutes. At this time N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (50.0 mg, 124 μmol) dissolved in 2.0 mL of dichloromethane was added and the reaction was stirred at room temperature for 3 hr. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized. It was then stirred overnight in 2.0M hydrochloric acid in ether (310.3 μl, 5 eq). The solvents were evaporated under a stream of nitrogen and lyophilized to afford the title compound as a white solid in 43.0% yield. LCMS m/z (%)=452 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 2.83 (s, 3 H), 2.90 (s, 3 H), 3.61-3.67 (m, 2 H), 3.82 (s, 2 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 4.07 (t, J=4.55 Hz, 2 H), 6.42 (d, J=2.53 Hz, 1 H), 6.99 (d, J=8.59 Hz, 1 H), 7.10 (dt, J=4.55, 2.53 Hz, 1 H), 7.40 (d, J=5.05 Hz, 2 H), 7.44 (s, 1 H), 7.57 (dd, J=9.09, 2.53 Hz, 1 H), 7.70 (d, J=2.53 Hz, 1 H), 7.82 (d, J=2.53 Hz, 1 H)