Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([NH2:7])CCCCC1.C(S(C[C@@H:16]([CH2:20][C:21]1[C:30]2[C:25](=CC=CC=2)[CH:24]=[CH:23][CH:22]=1)C(O)=O)(=O)=O)(C)(C)C>>[C:21]1([C@H:20]([NH2:7])[CH3:16])[CH:30]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC1CCCCC1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1cccc2ccccc12)C(=O)O
Product: C[C@@H](N)c1ccccc1

Procedure:
3-Substituted 2-sulfonylmethylpropionic acids have been prepared in moderate e.e. (enantiomeric excess), i.e. up to around 80% e.e. in two steps, from the corresponding allyl sulfides, by sequential asymmetric hydrogenation and oxidation at sulfur (DE-A-4233100; Jendralla, Tetrahedron: Asymmetry (1994) 5:1183-1186; Beck et al, Tetrahedron (1994) 50:4691-4698; Jendrella, Proceedings of Chira Tech '97 (The Catalyst Group). The requisite allyl sulfides are normally prepared as E/Z mixtures by a Wittig olefination reaction; subsequent separation of geometric isomers is required to give optimum results in the asymmetric hydrogenation process. For example, (E)-2-tert-butylthiomethyl-3-(1-naphthyl)acrylic acid was hydrogenated in methanol using a catalyst prepared from (S)-(−)-BINAP, benzeneruthenium (II) chloride dimer and NaOAc at 150° C. and 13800 kPa (2000 psi), followed by peracid oxidation to give (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid. Similar results were achieved via hydrogenation of the corresponding cyclohexylamine salt form. To access (S)-3-tert-butylsulfonyl-2-(1-naphthylmethyl)propionic acid in >99% e.e. required additional processing, with concomitant loss of yield, by crystallisation of diastereomeric salts formed with (R)-1-phenylethylamine.
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=CC=1)(=O)=O)CC#C.[NH:16]1C[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:17]([N:16]1[CH2:15][CH2:12][CH2:13][CH2:14][CH2:9]1)[CH2:18][C:19]#[CH:20]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#CCCN1CCCCC1
Temperature: 80 °C

Procedure:
A solution of toluene-4-sulfonic acid but-3-ynyl ester (45.0 g) and piperidine (40 mL) in ethanol (70 mL) was treated with a solution of potassium carbonate (27.8 g) in water (70 mL). The mixture was heated to 80° C. for 2 h, cooled to RT, and extracted with DCM (3×100 mL). The combined organic phases were dried (magnesium sulfate), and evaporated. Distillation of the residue (110° C., 30 mm Hg) gave the title compound as a colorless oil (17.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7](Cl)=O.[C:16]1([NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:22]>O1CCCC1>[NH:22]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:23]=[C:7]1[CH:6]=[CH:5][C:4]1[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH3:1])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(C=CC(=O)Cl)c1[N+](=O)[O-]
Reactant: Nc1ccccc1N
Solvent: C1CCOC1
Product: Cc1cccc(C=Cc2nc3ccccc3[nH]2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A tetrahydrofuran solution of 3.27 g of 3-methyl-2-nitrocinnamoyl chloride was dropped into a tetrahydrofuran solution of 3.41 g of o-phenylenediamine. The obtained mixture was stirred at room temperature for one hour to complete a reaction. Thereafter, the obtained solution was concentrated and extracted with ethyl acetate. The residue was heated in acetic acid at 100° C. for 2 hours to give 3.67 g of 3-[2-(1H-benzimidazol-2-yl)vinyl]-2-nitrotoluene.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][NH:6][CH:5]([CH:8]2[NH:13][C:12](=[O:14])[CH:11]([CH:15]3[CH2:20][CH2:19][CH:18]([Cl:21])[CH2:17][NH:16]3)[NH:10][C:9]2=[O:22])[CH2:4][CH2:3]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([N:6]1[CH2:7][CH:2]([Cl:1])[CH2:3][CH2:4][CH:5]1[CH:8]1[NH:13][C:12](=[O:14])[CH:11]([CH:15]2[CH2:20][CH2:19][CH:18]([Cl:21])[CH2:17][N:16]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:10][C:9]1=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1NC(C2CCC(Cl)CN2)C(=O)NC1C1CCC(Cl)CN1
Reactant: BrCc1ccccc1
Solvent: CC(C)=O
Product: O=C1NC(C2CCC(Cl)CN2Cc2ccccc2)C(=O)NC1C1CCC(Cl)CN1Cc1ccccc1
Reaction time: 24 h

Procedure:
One mole of 3,6-bis(5-chloro-2piperidinyl)-2,5-piperazinedione is stirred in 150 parts of acetone and 2.2 moles of benzyl bromide is added. The mixture is stirred 24 hours and refluxed 24 hours. The solvent is removed in vacuo and treated as in the preparation of 3,6-bis-(1-methyl-5-chloro-2-piperidinyl)-2,5-piperazinedone.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([C:13]1([CH2:17][OH:18])[CH2:16][O:15][CH2:14]1)[CH3:12].N1C=CC=CC=1>CCOCC>[CH2:11]([C:13]1([CH2:17][O:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:16][O:15][CH2:14]1)[CH3:12]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CCC1(CO)COC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC1(COC(=O)c2ccc(I)cc2)COC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-iodobenzoyl chloride (11.5 gms) in dry ether (50 ml) was added to a stirred solution of 3-ethyl-3-hydroxymethyloxetane (5 gms) and pyridine (3.5 mls) in ether (100 ml) at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 24 hours. After this time the mixture was washed with water and brine. The organic extracts were dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue was purified by column chromatography on silica (preeluted with 1% triethylamine in hexane) and eluted with 5% ethyl acetate in hexane. 3-Ethyl-3-(4-iodobenzoyloxymethyl) oxetane was obtained as a colourless oil (8.1 gms).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH2:17][C:18](=[C:22]=[O:23])[CH:19]=[CH:20][CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[C:26]1([NH2:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:23])[NH:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=1)[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(C1=CC=CC(=C=O)C1)N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)Nc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.3 %

Procedure:
A mixture of 2-(3-carbonyl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (720 mg, 2 mmol), phenylamine (224 mg, 2.4 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.14 g, 3 mmol) in dichloromethane (5 mL) and triethyl-amine (0.7 mL, 5 mmol) was stirred at 25° C. for 12 h. Then the reaction mixture was extracted with dichloromethane (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-phenylcarbamoyl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.8 g, 93%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C27H28N2O3 (M+H)+: 429.54, observed: 429.1.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[CH3:36][S:37][C:38](=[NH:40])[NH2:39]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:39]=[C:38]([S:37][CH3:36])[N:40]=2)[CH2:3][CH2:2]1
Reactant: CSC(=N)N
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (200 mg, 0.618 mmol) in DMF (5.154 ml) was added potassium carbonate (256 mg, 1.855 mmol) and 2-methyl-2-thiopseudourea sulfate (129 mg, 0.928 mmol). The reaction was warmed to 120° C. and stirred for 1 hr. The solvent was evaporated and the crude residue partitioned between DCM and water. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude product was purified by flash chromatography with a gradient of 2-10% MeOH in DCM and further purified reverse phase HPLC with a gradient of 10-100% MeCN in H2O to give 7.8 mg of the desired product as a white solid. HRMS (ES+)=351.1391. UV-LC: 100/100% UV purity at 214/254 nm; HPLC: tR=3.38 minute over 7.75 minutes. 1H NMR (400 MHz, MeOD) δ ppm 0.10-0.14 (m, 2H) 0.41-0.47 (m, 2H) 1.03-1.15 (m, 1H) 2.63 (s, 3H) 2.94 (d, J=7.07 Hz, 2H) 7.18 (d, J=5.56 Hz, 1H) 7.83 (d, J=7.07 Hz, 2H) 8.31 (d, J=7.07 Hz, 2H) 8.64 (s, 1H) 8.65 (d, J=5.05 Hz, 1H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)(=[O:9])[CH3:8].[CH3:32][O:33][CH2:34][CH2:35]Br>CN(C=O)C>[C:7]([O:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:35][CH2:34][O:33][CH3:32])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1)(=[O:9])[CH3:8]
Reactant: COCCBr
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Nc3ccc(C)c(OC(C)=O)c3)c2cc1OC
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 84.3 %

Procedure:
Potassium carbonate (2.2 g, 16 mmol) was added to a solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline (1.51 g, 4 mmol) in DMF (30 ml) and the mixture stirred for 15 minutes. 2-Bromoethyl methyl ether (667 mg, 4.8 mmol) was then added dropwise. The mixture was stirred for 1 hour at ambient temperature, then heated at 60° C. for 17 hours and finally allowed to cool. The insoluble material was removed by filtration and the filter pad washed with DMF. The filtrate was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5 followed by 93/7). The purified product was triturated with ether to give 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinazoline (1.34 g, 84%) as a white powder.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: O=C(CCCCCl)c1ccccc1Br
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]([CH3:17])[CH3:16].O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:12][CH2:13][CH:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:15]([CH3:17])[CH3:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamoate (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)-sulfonyl]oxy]methyl]-2-methylpropyl]carbamate (68%) (interm. 13).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][CH:12]([CH:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]([CH:15]([OH:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:13][OH:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCCCCCCCCCCCCCC(O)C(N)CO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCC(O)C(CO)Nc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Yield: 25.7 %

Procedure:
13 g (0.092 mol) of 4-fluoronitrobenzene, 30 g (0.099 mol) of 2-aminooctadecane-1,3-diol and 11 g (0.104 mol) of sodium carbonate were introduced into a 250 ml reactor equipped with a condenser. The reaction mixture was maintained at 120° C. for 3 hours. 200 ml of water were added slowly to the reaction medium, which was then poured into 500 ml of ice-cold water. The precipitate formed was filtered off on a sinter funnel and dried under vacuum at 50° C. in the presence of P2O5. After recrystallization twice from ethanol, 10 g of yellow powder were isolated.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:9][N:10]([CH:12]=O)[CH3:11]>>[CH3:9][N:10]([CH3:12])[CH:11]=[C:2]([CH2:3][CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CN(C)C=O
Reactant: CCCC(=O)OCC
Product: CCOC(=O)C(=CN(C)C)CC

Procedure:
In a distillation apparatus, 86 g of t-butylaminal ester and 87 g of ethyl butyrate in 100 ml of DMF were heated so that the alcohol distilled off slowly. Distillation of the product gave 73.8 g of ethyl β-dimethylamino-2ethylacrylate, corresponding to 87.3% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12]O.P(Br)(Br)([Br:16])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][Br:16]
Reactant: O=P(Br)(Br)Br
Reactant: Cc1c(CCO)cccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1c(CCBr)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitrophenyl ethyl alcohol (100 g) is added to toluene (500 ml). POBr3 (190 g) is added to the reaction mixture and refluxed for 2 to 3 hrs. Toluene is distilled off completely to give 2-Methyl-3-nitro phenylethyl bromide
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[N:4][CH:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCCN1CCCC1
Temperature: 100 °C
Yield: 38 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (60 mg, 0.187 mmol), 4-fluoro-5-hydroxy-2-methylindole (46 mg, 0.28 mmol) and cesium carbonate (121 mg, 0.37 mmol) in DMA (2 ml) was heated at 100° C. for 2 hours. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methanol/methylene chloride (5/95) followed by methanol saturated with ammonia/methylene chloride (5/95). The fractions containing the expected product were combined and evaporated. The residue was triturated with a mixture of pentane/ether. The solid was filtered, washed with pentane and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)cinnoline (32 mg, 38%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([B:17]([CH:19]([O:26][CH:27]([B:34]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[C:38]([Cl:43])[CH:37]=2)[OH:35])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)O)[CH:13]=[CH:14][C:15]=1[CH3:16]>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([B:17]([CH:19]([O:26][CH:27]([B:34]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[C:38]([Cl:43])[CH:37]=2)[O:35][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:1][CH2:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: OCC1CCCCN1
Reactant: Cc1ccc(B(O)C(OC(B(O)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl
Solvent: CCO
Product: Cc1ccc(B(OCC2CCCCN2)C(OC(B(OCC2CCCCN2)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl

Procedure:
The entitled compound (88 mg) was obtained by allowing 52 mg of 2-hydroxymethylpiperidine to act on 99 mg of bis(4,4′-(3-chloro-4-methylphenyl-hydroxyboryl)benzyl) ether in 1 mL of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]5[CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:37])[CH:12]=3)=[CH:10][C:3]=12.[OH-].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]5[CH:31]5[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]5)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:37])[CH:12]=3)=[CH:10][C:3]=12
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCCCC1C1CCNCC1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(Cl)ccnc4[nH]3)cn(C)c2cc1OCCN1CCCCC1C1CCNCC1
Yield: 85.9 %

Procedure:
4-Chloro-2-{1-methyl-5-methoxy-6-[2-(4-piperidylpiperidin-1-yl)ethoxy]-1H-indol-3-yl}-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 89a, but using 0.41 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-(4-piperidylpiperidin-1-yl)ethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 2.73 ml of a 5N aqueous potassium hydroxide solution. 0.272 g of 4-chloro-2-{5-methoxy-1-methyl-6-[2-(4-piperidylpiperidin-1-yl)ethoxy]-1H-indol-3-yl}-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [O:1]=[C:2]([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][N:4]([CH3:8])[CH2:5][CH2:6]O.S(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Cl:18][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3][C:2](=[O:1])[N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CN(CCO)CC(=O)N1CCCCCC1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CN(CCCl)CC(=O)N1CCCCCC1

Procedure:
A mixture of 5.7 g (27 mmol) of 2-{N-[2-oxo-2- (perhydro-1-azepinyl) ethyl]methylamino}ethanol, dissolved in 50 ml of chloroform, and 6 ml (excess) of thionyl chloride is heated under reflux for 2 h.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].I[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH3:20])[C:7]2=[O:12]
Reactant: O=C1NCCc2c(Cl)cccc21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(Cl)cccc2C1=O
Yield: 18.6 %

Procedure:
Using analogous reaction conditions as described in example 1, 5-chloro-3,4-dihydro-2H-isoquinolin-1-one (I-12d: 100 mg, 0.552 mmol) was reacted with 3-iodo-4-methyl-pyridine (121 mg, 0.552 mmol), 1,4-dioxane (6 mL), copper iodide (10.5 mg, 0.0552 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (23.51 mg, 0.165 mmol) and potassium phosphate (190.44 mg, 1.38 mmol) to afford the crude product. Purification by column chromatography on silica gel (35% ethylacetate in hexane) afforded 28 mg of the product (18% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O.Cl>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: N#CCCl
Reactant: O=C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#CC1OC12CCOCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of dihydro-2H-pyran-4(3H)-one (10.0 g) and 2-chloroacetonitrile (7.5 g) in tert-butanol (10 mL) was treated with 1.0 N potassium tert-butoxide (100 mL) drop-wise over 20 minutes. The reaction mixture was stirred at room temperature for 16 hours. It was diluted with water (10 mL) and 10% aqueous HCl (20 mL). The reaction mixture was concentrated to one-third of its original volume, and extracted with diethyl ether four times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel eluting with 20-40% ethyl acetate in hexanes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([OH:23])=O)=[C:16]([O:19][CH3:20])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:21]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)=[O:23])=[C:16]([O:19][CH3:20])[CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccncc1
Reactant: COc1cc2c(cc1C(=O)O)SCC[C@@H]2NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: COc1cc2c(cc1C(=O)Nc1ccncc1)SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 74.6 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-6-methoxythiochromane-7-carboxylic acid (300 mg), 4-aminopyridine (83.3 mg) and 2-chloro-1-methylpyridinium iodide (271 mg), the objective (S)-4-(tert-butoxycarbonylamino)-6-methoxy-N-(4-pyridyl)thiochromane-7-carboxamide (274 mg) was obtained as a pale-red amorphous solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[CH:16][C:15]=1[O:33][CH3:34]>CN(C)C=O>[CH:26]1([N:20]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:19])[C:17]2[CH:31]=[CH:32][C:14]([CH2:13][N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[CH:2]3)=[C:15]([O:33][CH3:34])[CH:16]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1CBr
Reactant: c1cnc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1Cn1cnc2ncccc21
Reaction time: 2 h

Procedure:
To a stirred solution of imidazo[4,5-b]pyridine (350 mg, 2.94 mmol) in N,N-dimethylformamide (25 mL), sodium hydride (118 mg, 60% dispersion in mineral oil, 2.94 mmol) was added. After stirring for 2 hr, 4-bromomethyl-3-methoxy-N,N-dicyclopentyl benzamide (1.4 g, 3.57 mmol) was added in small installments over 10 min. The reaction mixture was stirred under argon at 25° C. After 18 h, the reaction was quenched by adding acetic acid (0.5 mL) and the solvent was removed under reduced pressure at <45° C. The crude mixture (2 g) was chromatographed (silica gel, CH2Cl2 -MeOH-NH4OH 90-10-1) to give the title compound. (160 mg, 13%) DSC 198° C.; Anal calcd. for C25H30N4O2 ·0.7H2O: C, 69.65; H, 7.34; N, 12.99. Found C, 69.72; H, 7.39; N, 12.63.