Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[NH:38][CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4.C(N(CC)CC)C>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[N:38]([C:16]([C:12]4[CH:11]=[C:10]5[C:15](=[CH:14][CH:13]=4)[NH:7][CH:8]=[CH:9]5)=[O:18])[CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)c1ccc2[nH]ccc2c1)CC3
Temperature: 25 °C
Reaction time: 10 h
Yield: 27 %

Procedure:
Oxalyl chloride (15 ul, 0.14 mmol) at RT was added to a solution of indole-5-carboxylic acid (0.02 g, 0.12 mmol) in THF (1 ml). After stirring at RT for 10 h, the mixture was added THF (1 ml) followed by (+)-3-methoxy-morphinan hydrochloride (0.04 g, 0.12 mmol), then triethylamine (0.1 ml, 0.7 mmol) was added and stirred for 18 h. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was washed with saturated Na2CO3 (5 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give a crude pale brown oil. The crude product was purified by column chromatographed eluting with (MeOH: CH2Cl2=1:10) to give a pale yellow oil (0.013 g, 28% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[N:16]=O.[CH:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[N:20]1([C:18]2[NH:16][C:3]3[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Reactant: O=CN1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(N3CCOCC3)nc2n(CCC)c1=O
Reaction time: 12 h

Procedure:
7.9 g (0.033 mol) of 6-amino-5-nitroso-1,3-dipropyluracil and 5.0 g (0.049 mol) of N-formylmorpholine are dissolved in 40 ml of carbon tetrachloride. At ambient temperature, 7.5 g (0.049 mol) of phosphorus oxychloride are added, the mixture is heated to reflux temperature for one hour and left to stand at ambient temperature for about 12 hours. The oil which separates off on the surface is removed, dissolved in 50 ml of dichloromethane and poured onto ice together with the remaining solution, which has been concentrated by half. After neutralisation of the aqueous phase the organic phase is separated off and the aqueous phase is extracted with dichloromethane. From the combined organic phases the title compound is obtained, after drying and evaporation, as a crystalline residue which is recrystallised from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13].C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:3]=1[F:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1COc2c(ccc(F)c2F)N1
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OCC1C)C(=O)OCC
Reaction time: 1.17 h
Yield: 113.9 %

Procedure:
To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine was added 1.5 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130° to 140° C. for 70 minutes. The reaction mixture was subjected as such to column chromatography using 50 g of silica gel and eluted with chloroform to obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[1,4]benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by stirring at 50° to 60° C. for 40 minutes. To the reaction mixture were added ice and an aqueous solution of sodium bicarbonate, and the reaction product was extracted three times with 150 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. When a solid began to precipitate, a small amount of diethyl ether was added thereto, and the precipitate was collected by filtration. The precipitate was washed with a small amount of diethyl ether to yield 1.32 g of (-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:19]=[CH:18][C:17]([N:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=[O:26])=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:9]=1
Reactant: COC(=O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CN=[N+]=[N-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-n2ccccc2=O)ccc1-n1cnc(CN)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate prepared above (25 mg, 0.071 mmol) in THF (1 mL) and H2O (0.025 mL, 1.4 mmol), Ph3P (64 mg, 0.24 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give methyl 2-(4-(aminomethyl)-1H-imidazol-1-yl)-5-(2-oxopyridin-1(2H)-yl)benzoate as a crude mixture, which was then used in the next transformation. MS 325.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([OH:29])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[OH-:32].[Na+].C(Cl)(Cl)Cl>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18](=[O:19])[N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[C:16]([CH:15]=2)[O:29][C:17]([CH3:27])([CH3:16])[C:18]([OH:19])=[O:32])=[CH:30][CH:31]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C

Procedure:
A stirred, refluxing mixture of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol), sodium hydroxide (480 mg, 1.2 mmol), and 50 mL of acetone is treated with chloroform (125 μL, 1.6 mmol) in 20 mL of acetone. The reaction is refluxed for 4 hours and concentrated in vacuo. The resulting material is partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The resulting material is purified by chromatography on silica gel (20 g) with 40-100% ethyl acetate/hexane followed by 10% MeOH/ethyl acetate as the eluent to afford 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid as colorless foam. A stirred, 0° C. solution of 5-[5-[4-cyanophenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetic acid (210 mg, 0.411 mmol) in 2.0 mL of anhydrous dichloromethane and 150 mL of anhydrous ethanol at 0° C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and the resulting solution is concentrated in vacuo. The resulting ethyl 4-[5-[3-ethoxycarbonyldimethylmethoxy-4-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride is then dissolved in 50 mL of anhydrous ethanol in a pressure tube, and treated with anhydrous ammonia for 5 minutes at 0° C. The pressure tube is sealed and heated to 100° C. for 1 hour. Upon cooling and concentrating in vacuo, the resulting material is purified by chromatography on silica gel (15 g) with 5-20% methanol/dichloromethane as the eluent to afford ethyl 5-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-[N,N-bis(1-methylethyl)carbamoyl]phenoxydimethylacetate monohydrochloride as colorless foam; CHN calculated for C31H46CIN3O6 -1.25 H2O:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH:18]=[C:17]([I:19])[CH:16]=[C:15]2[CH2:20][OH:21])(=O)=O)=CC=1.[H-].[Na+]>O1CCCC1>[I:19][C:17]1[CH:16]=[C:15]2[N:14]([CH:18]=1)[CH2:13][CH2:12][O:21][CH2:20]2
Reactant: Cc1ccc(S(=O)(=O)OCCn2cc(I)cc2CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1cc2n(c1)CCOC2
Temperature: 25 °C
Reaction time: 36 h
Yield: 67.1 %

Procedure:
A solution of 2-[2-(hydroxymethyl)-4-iodo-pyrrol-1-yl]ethyl 4-methylbenzenesulfonate (2.0 g, 4.79 mmol) in tetrahydrofuran (15 mL) was slowly added to a suspension of sodium hydride (120 mg, 60% dispersion in mineral oil; 4.75 mmol) in tetrahydrofuran (5 mL) and stirred at room temperature for 36 h. The reaction was quenched with water and extracted with diethyl ether. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was purified by column chromatography over silica gel using 2% ethyl acetate in petroleum ether to afford 7-iodo-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine (800 mg, 66%) as a colorless crystalline solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[CH2:32]O)=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:20][CH2:32][CH:31]=[CH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][C:26]=1[N+:34]([O-:36])=[O:35]
Reactant: BrBr
Reactant: COc1ccc(/C=C/CO)c([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C=CCBr)c([N+](=O)[O-])c1
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
To a stirred slurry of triphenyl phosphine (16.4 g, 0.627 mol) in dry DCM (150 mL) under nitrogen at 0° C., is added dropwise a solution of bromine (3.2 mL, 0.0627 mol) in DCM (30 mL). After stirring for 15 min, a solution of (2E)-3-(4-methoxy-2-nitrophenyl)prop-2-en-1-ol (10 g, 0.044 mol) in dry DCM (100 mL) is added dropwise to the reaction mixture followed by a dropwise addition of pyridine (5.05 mL, 0.06 mol) at 0° C. After stirring at room temperature for another 4 h, the reaction mixture is quenched with ice and the product extracted with DCM. The organic layer is washed with water then brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by chromatography using silica-gel (60-120 mesh) and petrol ether/EtOAc as eluent to afford (7 g, 53%) of the title compound as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.52-7.55 (m, 1H), 7.42-7.47 (m, 1H), 7.11-7.16 (m, 1H), 7.06-7.09 (m, 1H), 6.23-6.29 (m, 1H), 4.15-4.18 (m, 2H), 3.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH:35]=O)[CH2:31][CH2:30]1)[CH2:26][CH2:27][CH3:28].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31]1
Reactant: CCCC[C@H]1CC[C@H](C=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@H](C=C(Br)Br)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A solution, cooled to -20° C., of 398 g of tetrabromomethane in 1 l of methylene chloride was treated dropwise under nitrogen gasification within 30 minutes with a solution of 629.6 g of triphenylphosphine in 1 l of methylene chloride. The mixture was subsequently stirred at -10° C. for a further 30 minutes, then treated dropwise within 30 minutes with a solution of 101 g of trans-4-butylcyclohexanecarboxaldehyde in 500 ml of methylene chloride and stirred at -5° C. for a further 2 hours. The mixture was poured into 4 l of hexane, the resulting mixture was stirred at -20° C. for 1 hour and then the precipitate was filtered off under suction and rinsed well with 1 l of cold (-20° C.) hexane. The filtrate was concentrated to a volume of about 1 l on a rotary evaporator, diluted with 2 l of hexane, again concentrated to a volume of about 1 l and stirred at -20° C. for a further 30 minutes. The precipitate was filtered off under suction and rinsed well with 700 ml of cold (-20° C.) hexane. The filtrate was freed from solvent on a rotary evaporator and the resulting yellow oil (195 g) was filtered chromatographically on silica gel with about 3 l of hexane. The eluate was evaporated up to constant weight on a rotary evaporator, there being obtained 171.3 g (88.1%) of trans-1-(2,2-dibromovinyl)-4-butylcyclohexane as a colourless liquid; Rf-value (hexane) 0.55.
Reaction SMILES: Cl.[C:2]([CH2:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)#[N:3].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:2]([CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6]1)#[N:3]
Reactant: N#CCC1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#CCC1CCN(S(=O)(=O)c2ccc(Cl)cc2)C1
Yield: 101.1 %

Procedure:
Acylation, in chloroform, of 36.6 g (0.25 mol) of 3-cyanomethylpyrrolidine hydrochloride with 52.7 g (0.25 mol) of para-chlorophenylsulfonic acid chloride, in the presence of 50.5 g (0.5 mol) of triethylamine makes it possible to obtain 72 g of a solid which is purified by chromatography on silica, Merck 70-230 mesh, using as eluent a dichloromethane/methanol mixture (99/1 v/v).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O>>[F:17][C:18]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1cccc(F)c1F
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccc(F)c2F)o1
Yield: 35 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,3-difluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 108 mg, 35%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35]>CN(C=O)C>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1CCC(c2ccc(O)cc2)=NN1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc2)=NN1
Temperature: 100 °C

Procedure:
A mixture of 2.00 g (10.5 mmol) of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, prepared as described in Example 13, 1.60 g (11.6 mmol) of anhydrous K2CO3, and 3.39 (1.26 mmol) of N-(bromopropyl)phthalimide in 43 ml of DMF is heated at 100° C. for 3 hrs under N2. The DMF is removed under vacuum and the residue taken up in 125 ml of EtOAc and 50 ml of water. The organic phase is washed with 50 ml of 5% aqueous NaOH, then with saturated NaCl, dried (MgSO4), and the solvent removed to leave a yellow solid. This solid is recrystallized from EtOAc to give 2.748 g of 6-[4-(3-phthalimidopropyloxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 69%.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>C1COCC1.CCOC(C)=O>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a mixture of 4.7 mL (9.43 mmol) of dimethylamine (2N in THF) and 2.6 mL (18.86 mmol) of TEA in 20 mL of THF is added dropwise, at 0° C., a solution of 2 g (9.43 mmol) of 6-chloropyridine-3-sulfonyl chloride (prepared according to patent WO 9840332) in 5 mL of THF. After stirring for 40 minutes at 0° C., the reaction medium is taken up in 40 mL of EtOAc, washed with water (2×40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. 1.93 g of 6-chloro-N,N-dimethylpyridine-3-sulfonamide are obtained in the form of a brown solid, which is used without further purification in the following step.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:16])([CH3:15])[C:4]=2[CH:3]=1.[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:17]([C:18]4[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=4[C:20]([OH:22])=[O:21])=[O:27])=[CH:7][C:6]=3[C:5]2([CH3:16])[CH3:15])=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)c2ccccc2-c2ccc(Br)cc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)c2cc(Br)ccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.9 %

Procedure:
2-bromo-9,9-dimethyl-9H-fluorene (40 g, 0.146 mol) and phthalic anhydride (23.8 g, 0.161 mol) were placed in a reaction vessel and dichloromethane (1 l) was added thereto. Then, aluminum chloride (29.2 g, 0.219 mol) was gradually added at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, distilled water was gradually added, and the reaction solution was extracted with dichloromethane and 3 times washed with distilled water. After solvent removal, the resultant solid was placed in a hexane(2 l)-containing vessel, washed, filtered and dried to give 2-(7-bromo-9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (50.4 g, yield 82%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[N:12]=[CH:13][N:14]([CH3:17])[C:15]=2Br)[CH:6]=1)=[O:4].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2B(O)O)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[C:15]2[N:14]([CH3:17])[CH:13]=[N:12][C:11]=2[C:7]2[CH:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][N:8]=2)[CH2:19][CH2:20]1
Reactant: OB(O)c1c(F)cccc1OCC1CC1
Reactant: COC(=O)c1ccnc(-c2ncn(C)c2Br)c1
Product: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1c(F)cccc1OCC1CC1
Yield: 3 %

Procedure:
The title compound was prepared in 3% yield from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carboxylic acid methyl ester and 2-(cyclopropylmethoxy)-6-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A followed by hydrolysis. 1H NMR (400 MHz, DMSO-d6): δ 0.12 (2H, m), 0.33-0.40 (2H, m), 0.83-0.94 (1H, m), 3.60-3.70 (1H, m), 3.72-3.84 (1H, m), 6.84 (1H, t, J=8.4 Hz), 6.92 (1H, d, J=8.2 Hz), 7.35 (1H, t, J=5.0 Hz), 7.40 (1H, t, J=7.8 Hz), 7.86 (1H, s), 8.08 (1H, d, J=4.7 Hz), 8.27 (1H, s). [M+H] Calc'd for C20H18FN3O3, 368. Found, 368.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[CH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Fc1ccc2[nH]cc(C=Cc3cccnc3)c2c1
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2[nH]cc(CCc3cccnc3)c2c1
Reaction time: 18 h
Yield: 49.9 %

Procedure:
A solution of 5-fluoro-3-(2-pyridin-3-yl-vinyl)-1H-indole (3 mmol) in MeOH (10 mL) is treated with Pd/C (200 mg) and shaken in a Parr apparatus under 40 atm of H2 for 18 h. The mixture is filtered through Celite and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0%-10% MeOH in DCM to afford 5-fluoro-3-(2-pyridin-3-yl-ethyl)-1H-indole (360 mg, 50%, 2 steps).
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17].[CH3:30][NH2:31]>CO>[CH3:30][NH:31][C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: CN
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(Cl)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: CC(=O)O
Product: CNC1=C2CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 0.5 h

Procedure:
To obtain the corresponding 4-methylamino compound, a suspension of (20S)-4-chloro-21-hydroxy-20-methylpregn-4-en-3-one acetate in methanol was mixed with 40% aqueous methylamine and refluxed for 30 minutes. Additional 40% aqueous methylamine was added and refluxing was continued for another 30 minutes. The solvent was then evaporated and the residue was purified as described above for the 4-amino compound to give (20S)-4-(methylamino)-21-hydroxy-20-methyl-pregn-4-en-3-one.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[CH:28][C:29]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:33])=[O:34])=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Product: CN(C)S(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 4-bromo-N,N-dimethyl-benzenesulfonamide (example B.25) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 74%). MS (ISP) 521.3 [(M+H)+]; mp 211–212° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][CH2:10][CH2:11][N:12]([CH2:24][CH2:25][N:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])[CH2:13][CH2:14][N:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].[BH4-].[Na+]>CO.C(Cl)Cl>[OH:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][CH2:14][CH2:13][N:12]([CH2:11][CH2:10][NH:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34]
Reactant: Oc1ccccc1C=NCCN(CCN=Cc1ccccc1O)CCN=Cc1ccccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Oc1ccccc1CNCCN(CCNCc1ccccc1O)CCNCc1ccccc1O
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of N, N, N-tris[[[(2-hydroxyphenyl)methylene]amino]ethyl]amine (40.0 g, 87 mmol) in 250 mL of methanol and 250 mL of methylene chloride was cooled in an ice bath. Sodium borohydride (10.0 g, 263 mmol) was added in several portions. Stirring was continued at room temperature for two hours. The solvents were evaporated and the residue was taken up in ether. This solution was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to afford N, N, N-tris[[[(2-hydroxyphenyl)methyl]amino]ethyl]amine(30.0 g, 74%) as a colorless glass.