Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:30](=[O:34])[C:31]([NH2:33])=[O:32])=[C:9]([CH2:28][CH3:29])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>[OH-].[Na+].CO>[NH2:33][C:31](=[O:32])[C:30]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]=1[CH2:28][CH3:29])=[O:34]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 59.3 %

Procedure:
A mixture of 600 mg (1.3 mmol) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester in 8 mL of 1N NaOH and 20 mL of MeOH was heated to maintain reflux for 0.67 hours, concentrated at reduced pressure and the residue taken up in EtOAc/water. The aqueous layer was separated, made acidic with 1N HCl and extracted with EtOAc. The EtOAc solution was dried (MgSO4) and evaporated and the residue crystallized from MeOH to give 352 mg (59% yield) of [[3-(2-amino-1,2-dioxoethyl)-1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-1H-indol-4-yl]oxy]acetic acid, mp, 211°-214° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>CN(C=O)C>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(F)cc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in dry DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added all in one portion. The mixture was stirred for 10 minutes at room temperature before 4-fluorobenzenesulfonyl chloride (12 mg, 0.062 mmol) was added. The reaction mixture was stirred for 10 minutes, and TFA (1 mL) was added dropwise. The reaction mixture was heated at 50° C. overnight and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.8 mg) in the form of the trifluoroacetate salt. MS m/z 381 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:27])[CH2:18][O:19]CC3C=CC=CC=3)[CH:12]=2)[CH:7]=1)[CH3:5]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17](=[O:27])[CH2:18][OH:19])[CH:12]=2)[CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc2cc(OC(=O)COCc3ccccc3)ccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1ccc2cc(OC(=O)CO)ccc2c1
Reaction time: 4 h
Yield: 78.7 %

Procedure:
2-[6-(2-Benzyloxyacetoxy) naphthalen-2-yl]propionic acid methyl ester 99 (5 g, 13.22 mmol) was dissolved in ethyl acetate (50 ml) in a pressure vessel, palladium on carbon (5%, 3 g) added and the mixture stirred under a hydrogen atm. (3.5 Kg) for 4 hrs. The catalyst was removed by filtration and ethyl acetate distilled off under vacuum. Hexane was added to precipitate and filtered to give pure 100 (3 g, 78.9%) as off-white powder. M.p: 49.5-52° C.
Reaction SMILES: [N+](C1C=CC=CC=1S([N:13]1[CH2:18][CH2:17][N:16]([C:19]2([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20]2)[CH2:15][CH2:14]1)(=O)=O)([O-])=O.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.Br[C:40]1[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=1>CN(C)C=O.C(OCC)(=O)C>[F:47][C:46]([F:49])([F:48])[C:43]1[CH:44]=[CH:45][C:40]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3([C:22]([O:24][CH3:25])=[O:23])[CH2:20][CH2:21]3)[CH2:17][CH2:18]2)=[N:41][CH:42]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CC2)CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 1-[4-(2-nitrobenzenesulfonyl)-piperazin-1-yl]-cyclopropanecarboxylate (0.60 g, 1.63 mmol) from Example 16C in anhydrous dimethylformamide (5 mL) was treated with potassium carbonate (0.67 g, 4.88 mmol) and thiophenol (0.21 g, 1.95 mmol) and stirred one hour at room temperature. This reaction mixture was then treated with 2-bromo-5-trifluoromethylpyridine (0.44 g, 1.95 mmol) and heated overnight at 80° C. Reaction diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 9:1 hexane:ethyl acetate to afford the title compound. MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].Cl.[CH3:11][NH2:12]>C1COCC1.CCN(C(C)C)C(C)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][CH3:11])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: -70 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
Cyanuric chloride (10 g, 54.3 mmol, 1 equiv.) was dissolved in THF (200 mL) and cooled to −70° C. DIPEA (36.3 mL, 1.42 mmol, 2 equiv.) and methylamine hydrochloride (3.7 g, 1 equiv.) were added to the reaction mixture, which was stirred 2 h at −70° C. and 1 h at rt. The THF was removed under reduced pressure and the remaining material was taken up in DCM and washed with water. The organic layer was dried with MgSO4 and the DCM removed to give a colourless powder (9.5 g, 97%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26]([O:31][CH2:32][CH3:33])(=[O:30])[O:27][CH2:28][CH3:29]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P:26](=[O:30])([O:31][CH2:32][CH3:33])[O:27][CH2:28][CH3:29])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCOP(=O)(CCCCCBr)OCC
Product: CCOP(=O)(CCCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O)OCC

Procedure:
The title compound was prepared from 7-benzyl-3-methylxanthine (0.059 mol) and diethyl 5-bromopentanephosphonate (0.07 mol) analogously to Example 23.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>COCCOC>[NH2:11][C:5]1[N:6]=[C:7]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:2]([Cl:1])=[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: COCCOC
Product: Nc1nc(NCCc2ccc(O)cc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and tyramine in DME. ES-MS m/e (%): 333 (M{37Cl}+H+, 40), 331 (M{35C}+H+, 100).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2noc3ccsc23)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(-c2noc3ccsc23)c1
Yield: 39.9 %

Procedure:
Eight grams of 3-(3-methoxyphenyl)thieno[2,3-d)isoxazole was stirred with 80 g of pyridine hydrochloride for nine hours under nitrogen at 140° C. The reaction mixture was then allowed to cool and quenched with water. The organics were extracted into ether/ethyl acetate (1:1), which was then washed once with 3N hydrochloric acid and three times with water an dried over anhydrous magnesium sulfate. Evaporation of the solvents left 4 g of an oil, which was passed through a silica gel column packed in hexane. Elution of the column with 5% ethyl acetate/dichloromethane and recrystallization of the resultant solid from ether/hexane gave 3 g of a solid, m.p. 114°-116° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30](Cl)(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1>O.C(#N)C>[CH3:19][C:20]1([CH3:34])[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([S:30]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][C@H:2]3[C:10]([OH:12])=[O:11])(=[O:32])=[O:31])[CH:28]=[CH:29][C:22]=2[O:21]1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCc2cc(S(=O)(=O)N3c4ccccc4C[C@H]3C(=O)O)ccc2O1
Yield: 73 %

Procedure:
1 g (6.13 mmol) of 2,3-dihydro-(2S)-1H-indole-2-carboxylic acid, and 0.97 g (7.05 mmol) of potassium carbonate are solubilised in 2 ml of water. 1.6 g (6.13 mmol) of 3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-sulfonyl chloride solubilised in 12 ml of acetonitrile and 2 ml of water are added. Agitation is allowed to take place for 5 hours at ambient temperature. Water is added to the reaction medium, washing is performed with ethyl acetate, the acidity of the aqueous phase is raised to pH 3 by a solution of hydrochloric acid 1 N, and then extraction is performed using ethyl acetate. The organic phases are collected, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol (9/1; v/v) mixture. The expected product is obtained in the form of a beige foam with a yield of 73%.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: OC1(c2cc(F)cc(F)c2)CCOCC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCOCC3)cc2F)OC1(C)C
Yield: 97 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol (1.0 equiv.) to give 4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol in 97% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.32-1.42 (m, 12 H), 1.56-1.65 (m, 2H), 2.11 (d, J=3.13 Hz, 2 H), 3.86-3.92 (m, 4 H), 6.99 (d, J=9.00 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][N:27]([S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:26][CH2:25]3)[N:21]=1)=[CH:5]2
Reactant: Clc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCNCC4)CS3)cc2c1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCN(CC[C@@H]2CSC(c3cc4cc(Cl)cc(NC5CCCC5)c4[nH]3)=N2)CC1

Procedure:
{5-Chloro-2-[(R)-4-(2-piperazin-1-yl-ethyl)-4,5-dihydro-thiazol-2-yl]-1H-indol-7-yl}-cyclopentyl-amine prepared in Example 160 and ethylsulfonylchloride were reacted according to the same procedure as Step B of Preparation 29 to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>CC(C)=O>[CH3:1][C:2]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)([CH3:6])[C:3]#[N:4]
Reactant: CC(C)(O)C#N
Reactant: C1COCCN1
Solvent: CC(C)=O
Product: CC(C)(C#N)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Acetone cyanohydrin (4.3 g, 50 mmol) was dissolved into acetone (5 mL). Morpholine (4.3 g, 50 mmol) was added and the solution was stirred at rt for 24 h. The volatile solvents were removed in vacuo to give the title compound as a clear liquid in quantitative yield. MS ESI 155.0 [M+H]+, calcd for [C8H14N2O+H]+ 155.1.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20](F)=[N:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([N:9]2[CH2:10][CH2:11][C:5]3=[N:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]2=3)=[N:21][CH:22]=1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Reactant: Fc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cn1)CC2
Temperature: 170 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (300 mg, 1.5 mmol), 5-chloro-2-fluoropyridine (600 mg, 4.5 mmol) and K2CO3 (621 mg, 4.5 mmol) in 10 mL of DMF was stirred at 170° C. for 30 min. After the solvent was removed in vacuo, the product was purified by flash chromatography eluting with DCM:MeOH=10:1 to give 6-(5-chloropyridin-2-yl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a yellow solid. (50 mg, 11.3%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:5][CH:4]=1)[CH3:2].P(Cl)(Cl)([Cl:28])=O.N>O>[Cl:28][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3nc[nH]c(=O)c23)cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Temperature: 25 °C

Procedure:
Stir a suspension of 20.0 g (0.06 mol) 5-(4-ethylphenyl)-6-(2-fluorophenyl)furo[2,3-d]pyrimidin-4(3H)-one in 100 ml (165 g, 1.07 mol) phosphoryl chloride for 1 h at 120° C. After cooling to room temperature, add the reaction solution dropwise to a mixture of 330 ml water and 610 ml 25% aqueous ammonia solution, stirring vigorously; a temperature rise to 55-65° C. is observed. Leave the reaction mixture to cool to room temperature. After extracting twice with 500 ml dichloromethane each time, wash the organic phase with satd. aqueous sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Mix the residue with 150 ml petroleum ether, filter, wash with ice-cooled petroleum ether and dry under vacuum. 18.7 g (90% purity, 80% of theor.) of the title compound is obtained.
Reaction SMILES: Br[C:2]1[C:19]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:18]([CH3:28])[C:5]2[CH:6]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=3)[CH2:7][O:8][C:4]=2[C:3]=1[CH3:29].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCCCCC.C(OCC)(=O)C>[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:6]2[C:5]3[C:18]([CH3:28])=[C:19]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:3]([CH3:29])[C:4]=3[O:8][CH2:7]2)=[CH:14][CH:13]=1)([CH3:16])[CH3:17]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c2c(c(C)c(NC(=O)CC(C)(C)C)c1-c1ccccc1)C(c1ccc(C(C)C)cc1)CO2
Yield: 42 %

Procedure:
Using N-(6-bromo-3-(4-isopropylphenyl)-4,7-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 87 and phenylboronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 42%. Melting point: 212-213° C. (hexane-ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[CH3:13]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:13])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CO
Product: COC(=O)c1ccc(OC)c(O)c1
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-4-methoxybenzoic acid (Aldrich, 10 g, 59.5 mmol), methanol (250 ml) and concentrated sulfic acid (1 ml) was stirred overnight and the product was poured into a mixture of sodium bicarbonate and ice. The aqueous mixture was then extracted three times with ethyl acetate. The resulting organic layers were combined, washed with water and brine, and dried over anhydrous magnesium sulfate. Rotary evaporation of the solution gave 9.5 g of the desired product as a colorless oil. NMR (δ):3.89 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:7][CH2:8][C:9]1[O:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:14]C1OC(CBr)=CC=1>CCOCC>[CH2:8]([O:7][CH2:1][C:2]1[O:6][C:5]([CH3:14])=[CH:4][CH:3]=1)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1coc(COCc2ccco2)c1
Reactant: Cc1ccc(CBr)o1
Solvent: CCOCC
Product: Cc1ccc(COCc2ccco2)o1

Procedure:
d. 5-Methyl-furfuryl furfuryl ether was prepared by the procedure described in J. E. Zanetti in J.Am.Chem.Soc. 49, 1066 (1927) for the difurfuryl ether, starting with 5-methyl-furfuryl bromide (Compt.Rend. 222, 1441 (1946)) instead of furfuryl bromide of Zanetti. The product was isolated by ether extraction of the crude mixture after having diluted with water. For purification the ether extract was distilled twice -- b.p. 68°-70° C. at 0.01 mm/Hg vacuum. The product was a viscous colourless liquid, darkening rapidly on contact with air.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:18]([O:20][P:21]([C:26]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:27]=1[NH2:28])([O:23][CH2:24][CH3:25])=[O:22])[CH3:19]>>[CH2:18]([O:20][P:21]([C:26]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:14]([NH:13][C:5]1[CH:4]=[C:3]([C:2]([F:16])([F:17])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=1)=[O:15])([O:23][CH2:24][CH3:25])=[O:22])[CH3:19]
Reactant: CCOP(=O)(OCC)c1cc(Br)ccc1N
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CCOP(=O)(OCC)c1cc(Br)ccc1NC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To an oven dried 30 mL vial containing a stirring bar 2 mL of pyridine was added followed by 3,5-bistrifluorometylphenylisocyanate (35 mg, 0.125) and 2-Diethylphosphono-4-bromoaniline (32 mg, 0.104 mmol). The resulting solution was stirred at 65° C. for 3 hours. Pyridine was removed by rotary evaporation and then the product was purified by silica column chromatography using mixtures of EtOAc and hexanes to give 1-(2-diethylphosphono-4-bromophenyl)-3-(3,5-bistrifluoromethylphenyl)urea. 1H-NMR (400 MHz, CDCl3): δ=1.32 (t, 6.8 Hz, 6H CH3), 4.10 (m, 4H, CH2), 7.52 (s, 1H, CCF3CHCCF3), 7,64 (m, 2H, CHCBRCH), 8.03 (s, 2H, CCF3CHCNH), 8.30 (m, 1H, CPCNCH), 8.62 (s, 1H, NH), 9.82 (s, 1H, PCCNH). 31P (400 Mz, CDCl3) δ=18.19 (s)
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH2:8][CH2:7]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:23]Br>C(Cl)Cl.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:23][C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][N:6]([Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:16])[CH3:15])[C:10]2=[N:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cccnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Yield: 76.7 %

Procedure:
To a stirred and cooled (0° C.) solution of the azaindoline 3 (1.1 g, 4.7 mmol) in CH2Cl2 (25 mL) and pyridine (0.46 mL, 5.6 mmol) was added dropwise a solution of bromine (0.24 mL, 4.7 mmol) in CH2Cl2 (15 mL) over a period of 13 min. After a further 20 min stirring the mixture was diluted with a NaHCO3—Na2S2O3 (1:1 v/v) solution and stirred vigorously for 50 min. The resulting mixture was partitioned and the aqueous layer extracted with CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by SGC with hexane:AcOEt as eluent (in gradient up to 1.3% AcOEt) to afford the bromo derivative 4 (1.13 g, 77%) as a pale yellow oil. 1H NMR (400 MHz; CDCl3) δ 0.31 (s, 6H), 0.95 (s, 9H), 2.99 (t, J=9.1 Hz, 2H), 3.67 (t, J=9.1 Hz, 2H), 7.20 (m, 1H), 7.79 (m, 1H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[CH2:26][C:25](=O)[CH2:24][CH2:23]2>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][CH:25]2[CH2:24][CH2:23][C:22]3[C:27](=[C:28]([F:30])[CH:29]=[C:20]([F:19])[CH:21]=3)[CH2:26]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.9, 14.1, 14.2, 19.5, 19.6, 28.2, 28.6, 28.7, 28.9, 29.6, 29.9, 36.5, 36.6, 51.9, 52.3, 60.1, 60.6, 62.9, 100.7, 100.9, 101.2, 104.2, 110.5, 110.6, 110.8, 118.2, 118.5, 132.4, 137.9, 138.0, 139.6, 139.9, 159.8, 162.1, 162.2, 172.2, 172.4; MS 419.2 m/z (M+1); Chiral Separation using Chiralpak AD column, elute 85:15 heptane:ethanol; Flow Rate 275 mL/min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:5][C:4]=2[N:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccn1)CC2=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(n1)CC(c1ccccn1)CC2=NNC(=N)N
Yield: 91.5 %

Procedure:
A mixture of 2,4-dimethyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.08 g), aminoguanidine hydrochloride (0.037 g), concentrated hydrochloric acid (0.079 ml), water (0.079 ml) and ethanol (10 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water-ethanol to give 5-guanidinoimino-2,4-dimethyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 87) (0.1 g) as colorless crystals.