Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=3[OH:40])[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].[OH-].[Na+].Br[CH2:48][CH:49]([CH2:52][CH2:53][CH2:54][CH3:55])[CH2:50][CH3:51]>COCCO>[CH2:1]([CH:3]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)[N:15]=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH2:48][CH:49]([CH2:50][CH3:51])[CH2:52][CH2:53][CH2:54][CH3:55])=[CH:35][C:34]=3[OH:40])[N:13]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCCCC(CC)COc1ccc(-c2nc(-c3ccc(OCC(CC)CCCC)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reactant: CCCCC(CC)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(-c2nc(-c3ccc(OCC(CC)CCCC)cc3)nc(-c3ccc(OCC(CC)CCCC)cc3O)n2)cc1
Reaction time: 0.25 h
Yield: 101.5 %

Procedure:
A 1 l sulfonating flask equipped with stirrer, condenser, internal thermometer and dropping funnel is charged at 80° C. with 83.7 g (0.14 mol) of 4-{4,6-bis[4-(2-ethylhexyloxy)phenyl]-s-triazin-2-yl}-1,3-dihydroxybenzene together with 500 ml of methylcellosolve. 18.1 g of 30% sodium hydroxide solution (0.16 mol) are added, stirring is continued for 15 minutes, and a solution of 31.4 g (0.16 mol) of 3-bromomethylheptane and 30 ml of methylcellosolve is then added dropwise over a period of 30 minutes. After 24 hours of stirring at 110° C., alkylation is complete (thin-layer chromatogram). The mixture is evaporated to dryness in vacuo, the residue is dissolved in 500 ml of toluene, the resulting solution is filtered, and the filtrate is extracted with water. The organic phase is dried over sodium sulfate and the solvent is distilled off to give 100.9 g of a red-brown oil. The crude product is dissolved in 200 ml of 97.5:2.5 toluene/ethyl acetate and purified by chromatographing it through silica gel (10 cm×40 cm). This gives 79.4 g (80% of theory) of the compound of the formula ##STR26## as a honey-like, red-brown resin.
Reaction SMILES: [Na+].[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([O-:17])(=O)=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([Cl:19])(=[O:17])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])c1ccc(C2CCCCC2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
The sodium salt prepared in Example I (420 gm, 1.6M) is intermittently mixed with phosphorous pentachloride (160 gm, 0.77M) in a three liter multi-necked flask and slowly warmed to 70° C. in an oil bath. The liquified reaction mass is aged at 70° C. for 8 hours, then cooled to room temperature and carefully poured over one kilogram of cracked ice. A solid precipitate is removed by filtration and the aqueous phase is extracted with methylene chloride three times, each time using 300 milliliters of MeCl. The combined organic phases are dried and concentrated using a rotary evaporator. 4-cyclohexylbenzenesulfonyl chloride (338 gm, 81% of theoretical yield) was recovered as a crude product.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([CH3:13])=[O:12])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[CH2:20][C:19]2=O.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[CH3:1][C:2]1[C:10]([S:11]([CH3:13])=[O:12])=[C:9]([C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:19]1[CH:18]2[CH2:25][CH:22]([C:21](=[O:26])[CH:20]=1)[CH2:23][CH2:24]2)=[O:5]
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(=O)OC2=CC(=O)C3CCC2C3)ccc(C(F)(F)F)c1S(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
250 mg (0.94 mmol) of 2-methyl-3-(methylsulfinyl)-4-(trifluoromethyl)benzoic acid were introduced into 25 ml of dry dichloromethane. Thereafter 143 mg (1.03 mmol) of bicyclo[3.2.1]octane-2,4-dione and subsequently, in portions, 216 mg (1.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The mixture was stirred at room temperature for 16 hours and then admixed with 5 ml of 1M hydrochloric acid. Following phase separation, the organic phase was freed from the solvent on a rotary evaporator. The residue was purified by chromatography, with 170 mg of clean product being isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C@H:12]([CH3:16])[CH2:13][CH2:14][N:25]=[N+:26]=[N-:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCBr)N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CCN=[N+]=[N-])N(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 96 h
Yield: 106.6 %

Procedure:
To a solution of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-bromopropyl]-benzenesulfonamide (1.74 g, 3.58 mmol) in THF/H2O (20/4, 24 mL) was added sodium azide (2.33 g, 35.8 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 4 days. The mixture was extracted with ether (3×60 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 1.53 g of 4-chloro-N-(2,5-difluorophenyl)-N-[(R)-1-methyl-3-azidopropyl]benzenesulfonamide as a colorless oil in 95% yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].O.S([O-])([O-])=[O:11].[Na+].[Na+].[N+]([O-])([O-])=O.[Pb+2].[N+]([O-])([O-])=O>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:2]
Reactant: CCc1ccccc1
Reactant: O=S([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [Pb+2]
Solvent: O
Product: CC(=O)c1ccccc1
Yield: 95 %

Procedure:
Ten millimoles of ethylbenzene were heated at 400° C. for 1 hour with 1.35 ml of water containing 20 millimoles of sodium sulfite and 10 millimoles of lead nitrate. On cooling, a suspension of black precipitate was observed. The reaction product was extracted with ether and the ether layer was dried over Na2SO4 and concentrated to yield acetophenone in more than 95% yield. Acetophenone was confirmed by NMR and gas chromatographic techniques.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][NH:10][C:8]=3[N:9]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:12]=[N:11][N:10]([CH2:25][CH2:26][NH:27][C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2CCNC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Ethyl 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (125 mg, 0.541 mmol) was dissolved in DMF (10 mL), followed by addition of potassium tert-butoxide (79 mg, 0.703 mmol). After stirring for 15 minutes, 1,1-dimethylethyl (2-bromoethyl)carbamate (121 mg, 0.541 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness. The crude residue was diluted with water (50 mL) and acidified with acetic acid. The contents were extracted with DCM (4×50 mL). The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 50% EtOAc:Hex). The final product was obtained as 0.114 g (56%). LCMS E-S (M+H)=375.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.14 (m, 4H), 1.15-1.20 (m, 2H), 1.27 (s, 7H), 1.41 (t, J=7.07 Hz, 3H), 2.36-2.45 (m, 1H), 3.31-3.41 (m, 3H), 4.36-4.50 (m, 5H), 6.84 (t, J=5.81 Hz, 1H), 7.65 (s, 1H), 8.24 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:12][CH3:13])=[C:6]([CH:8](O)[CH2:9][CH3:10])[CH:7]=1.CCN(S(F)(F)[F:22])CC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:12][CH3:13])=[C:6]([CH:8]([F:22])[CH2:9][CH3:10])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC(O)c1cc(Br)cc(OC)c1OC
Solvent: ClCCl
Product: CCC(F)c1cc(Br)cc(OC)c1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred solution of 1-(5-bromo-2,3-dimethoxyphenyl)propan-1-ol (400 mg, 1.45 mmol) in DCM (10 mL) at −78° C. was added DAST (0.58 mL, 4.36 mmol) and stirred the reaction for 10 min at −78° C., then warmed to 0° C. for 2 h. The reaction was quenched with water and saturated aqueous NH4Cl (100 mL), extracted with EtOAc, dried over NasSO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 30% EtOAc in hexanes as an eluent to furnish 5-bromo-1-(1-fluoropropyl)-2,3-dimethoxybenzene (80%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].C([O-])(=O)C.[Na+].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1.[OH-].[Na+]>>[C:14]([O:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: OCCCBr
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC(=O)OCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
90 g of 3-bromopropanol was added to 8 g of sodium acetate, to which 59.8 g of diketene was added dropwise controlling the reaction mixture at 40°-50° C. The mixture was further stirred at room temperature for 3 hours. The reaciton mixture was poured into ice water containing a diluted aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane and the dichloromethane layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 102.6 g of 3-bromopropyl acetoacetate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6](Br)[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2.[C:18]([Cu])#[N:19].[C-]#N.[K+].CO>O>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([C:18]#[N:19])[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2
Reactant: CC1CC(=O)Nc2nc(Br)c3ncccc3c21
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1CC(=O)Nc2nc(C#N)c3ncccc3c21
Yield: 70 %

Procedure:
2 g (0.007 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one, 0.3 g (0.003 mol) of CuCN and 0.3 g (0.005 mol) of KCN are heated for 7 hours at 160° C. in an autoclave with 20 ml of methanol and 10 ml of water. After cooling, the mixture is filtered under suction, and the residue digested in chloroform/methanol, 1:1, under reflux for 4 hours. The organic phase is filtered, dried and concentrated. The residue is purified by recrystallization from ethanol/petroleum ether, and 0.5 g (60.1% of theory) of 1-methyl-6-cyano-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one is obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:4][C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.[Cu](C#N)[C:32]#[N:33]>CN1C(=O)CCC1>[N:25]1([C:23]([C:3]2[C:2]([C:32]#[N:33])=[CH:22][C:6]3[O:7][C:8]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[O:9][C:5]=3[CH:4]=2)=[O:24])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: N#C[Cu]C#N
Reactant: O=C(c1cc2c(cc1Br)OC(c1ccccc1)(c1ccccc1)O2)N1CCOCC1
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(cc1C(=O)N1CCOCC1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 190 °C
Yield: 2583.3 %

Procedure:
A mixture of (6-bromo-2,2-diphenyl-benzo[1,3]dioxol-5-yl)-morpholin-4-yl-methanone, (204 mg, 0.437 mmol) and copper cyanide (102 mg, 1.139 mmol, 2.6 eq.) in N-methyl pyrrolidinone (3 mL) was heated at 190° C. during 16 h. The reaction mixture partitioned between water and ethyl acetate. The organic layer was washed with brine and evaporated in vacuo. Purification by flash chromatography afforded the title compound (4.656 g, 83 %) as an off white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:9]([N:11]1[C:19]2[CH:18]=[C:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH:16]=[C:15]([C:26]([O:28]C)=[O:27])[C:14]=2[CH2:13][CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C1COCC1>O>[C:1]([O:5][C:6]([C@@H:8]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:9]([N:11]1[C:19]2[CH:18]=[C:17]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH:16]=[C:15]([C:26]([OH:28])=[O:27])[C:14]=2[CH2:13][CH2:12]1)=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(-c2ccncc2)cc2c1CCN2C(=O)[C@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H](Cc1ccccc1)C(=O)N1CCc2c(C(=O)O)cc(-c3ccncc3)cc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
To a 20 ml vial were added (S)-methyl 1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylate 54.8.A (900 mg, 1.8 mmole), LiOH)(376 mg, 9.0 mmole), 40 ml of THF, and 10 ml of water. The reaction was stirred at 50° C. for 3 hour at which time the solvent was removed by a stream of nitrogen. The crude product was purified using a silica gel column (eluting with 10% MeOH in DCM) to give (S)-1-(2-(tert-butoxycarbonyl)-3-phenylpropanoyl)-6-(pyridin-4-yl)indoline-4-carboxylic acid 60.A as a yellow solid (403 mg, 46% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[N:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CN1CCOCC1>CO>[N:21]1([CH2:27][CH2:28][NH:29][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCCN1CCOCC1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCCN3CCOCC3)cc2s1
Yield: 44.2 %

Procedure:
the title compound (56 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 2-morpholin-4-ylethylamine (80 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 423.5 (M+1, 100%). Yield=43%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Cl[CH2:11][C:12]([N:14]=[C:15]=[O:16])=[O:13].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:16]=[C:15]1[NH:14][C:12](=[O:13])[CH2:11][N:1]1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: O=C=NC(=O)CCl
Reactant: N#Cc1cccc(N)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: N#Cc1cccc(N2CC(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
g of 3-Aminobenzonitril were dissolved in 60 ml Dioxan and 0.8 ml of Chloro-acetyl isocyanate added. The reaction mixture was stirred at rt for 2 h. 2.5 ml of DBU were added and the reaction mixture stirred at rt for 40 h. The product was extracted with DCM. MS(ISO): 202.2 (MH+)
Reaction SMILES: [OH:1][C:2]1[C:13]2=[C:14]3[CH:9]([CH2:10][C:11]4[CH:18]=[C:17]([OH:19])[C:16]([O:20][CH3:21])=[CH:15][C:12]=42)[NH:8][CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[O:22][CH3:23].C(=O)(O)[O-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CN(C)C=O>[CH2:31]([N:8]1[CH:9]2[C:14]3=[C:13]([C:2]([OH:1])=[C:3]([O:22][CH3:23])[CH:4]=[C:5]3[CH2:6][CH2:7]1)[C:12]1[CH:15]=[C:16]([O:20][CH3:21])[C:17]([OH:19])=[CH:18][C:11]=1[CH2:10]2)[CH:30]=[CH2:29]
Reactant: COc1cc2c(cc1O)CC1NCCc3cc(OC)c(O)c-2c31
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCc2cc(OC)c(O)c3c2C1Cc1cc(O)c(OC)cc1-3

Procedure:
582 mg. (1.85 mmol) (+)-5,6,6a,7-Tetrahydro-1,9-dihydroxy-2,10-dimethoxy-4H-dibenzo(de,g)quinoline are dissolved in 10 ml. dimethylformamide. After the addition of 385 mg. (4.58 mmol) sodium bicarbonate and 0.2 ml. (279.6 mg.; 2.31 mmol) allyl bromide, the reaction mixture is stirred for 30 minutes at ambient temperature and thereafter heated under reflux for 2 hours. Subsequently, the solvent is evaporated off in a vacuum and the residue is partitioned between chloroform and water. After working up and crystallising from chloroform/diethyl ether, there is obtained (+)-6-allyl-5,6,6a,7-tetrahydro-1,9-dihydroxy-2,10-dimethoxy-4H-dibenzo(de,g)quinoline; m.p. 161°-171° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][F:44])=[O:40])[CH:26]=[CH:27][C:28]=1B1OC(C)(C)C(C)(C)O1>>[F:22][C:23]1[CH:24]=[C:25]([NH:38][C:39]([NH:41][CH2:42][CH2:43][F:44])=[O:40])[CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@@H:16]2[CH3:21])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:6]=2[N:7]=1
Reactant: COC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Product: COC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCF)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 5 %

Procedure:
Method as described for example 147 using (S)-methyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 26) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 31) as starting materials. The crude reaction mixture was purified by SCX-2 cartridge (loaded in MeOH eluted with 2M methanolic ammonia). Ammonia eluent was concentrated in vacuo. Residue was then purified by prep. HPLC at low pH to afford a brown solid (10 mg, 0.02 mmol, 5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:7]([NH2:9])[CH:8]=1.Cl.[N:21]1([CH2:27][CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34](Cl)=O)=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:7]([NH:9][CH2:34][C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:38][CH:37]=2)[CH:8]=1
Reactant: COc1ccc(CCc2ccc(OC)cc2N)cc1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Product: COc1ccc(CCc2ccc(OC)cc2NCc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 73.2 %

Procedure:
Synthesized from 5-methoxy-2-[2-(4-methoxyphenyl)ethyl]phenylamine (643 mg) and 4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (989 mg) according to an analogous synthetic method to Example 152, the title compound (868 mg) was obtained.
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Reactant: CN(C)Cc1ccc(N)cc1
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Cl.[S:38]1[CH:42]=[C:41]([C:43]2[CH:50]=[CH:49][C:46]([CH2:47][NH2:48])=[CH:45][CH:44]=2)[N:40]=[N:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:48][CH2:47][C:46]1[CH:45]=[CH:44][C:43]([C:41]2[N:40]=[N:39][S:38][CH:42]=2)=[CH:50][CH:49]=1)=[O:24]
Reactant: NCc1ccc(-c2csnn2)cc1
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2ccc(-c3csnn3)cc2)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 4-(1,2,3-thiadiazol-4-yl)benzylamine hydrochloride.
Reaction SMILES: C[Si](C)(C)[N:3]=[S:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].CO>>[C:13]1([S:4](=[NH:3])([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)N=S(=O)(Oc1ccccc1)c1ccccc1
Solvent: CO
Product: N=S(=O)(Oc1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 95 %

Procedure:
Reactants used in the general procedure were phenyl N-trimethylsilylbenzenesulfonimidate (0.02 mol, 6.10 g) and methanol (0.06 mol, 2.5 ml). Reaction temperature was 22°-25° C.; reaction time was 4 hours. Stripping temperature was less than 35° C.; product yield was 95%. The 1H NMR spectrum of the product (200 MHz, 25% in CDCl3, 1 drop CH3CN) exhibited maxima at the following shift values: 3.78 (s, 1H, broad, NH); 6.88-8.01 (m, 10H, SC6H5, OC6H5).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32](O)=[O:33])=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]([NH:1][CH:2]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([F:11])=[CH:9][CH:10]=2)[OH:4])=[O:33])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) were added 4-fluoronaphthalenecarboxylic acid (311 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.43 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted-with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (558 mg, 76%).