Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][C:18](=[O:73])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:72])[NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:71]=[CH:70][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67](O)=[O:68])=[CH:48][CH:47]=2)=[O:45])=[CH:42][CH:41]=1.C(Cl)CCl>C(Cl)Cl>[O:9]=[C:10]1[CH:14]=[CH:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][C:18](=[O:73])[NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][C:34](=[O:72])[NH:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:41]=[CH:42][C:43]([C:44]([C:46]2[CH:51]=[CH:50][C:49]([NH:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:1][N:2]3[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[O:68])=[CH:48][CH:47]=2)=[O:45])=[CH:70][CH:71]=1
Reactant: O=C(O)CCOCCOCCOCCOCCNc1ccc(C(=O)c2ccc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN3C(=O)C=CC3=O)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
N-hydroxysuccinimide (438 mg, 4.00 mmol) was added to a solution of crude 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (3.00 g) in anhydrous DCM (20 ml) was added followed by EDC (946 mg, 5.00 mmol). The reaction was stirred at r.t. for 2-3 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH gradient) to provide 2.15 g (2.12 mmol) of 2,5-dioxopyrrolidin-1-yl 1-((4-(4-((1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,19-dioxo-7,10,13,16-tetraoxa-4,20-diazatricosan-23-yl)oxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>C1COCC1>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:9](=[O:10])[NH:11]2)=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(C)=O
Reactant: NC(=O)Nc1cccc(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(Cl)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
170 mg (1.0 mmol) N-[3-chlorophenyl]urea, 100 mg (0.77 mmol) 4-cyanobenzaldehyde and 100 mg (0.77 mmol) ethyl 3-oxobutanoate are suspended in 2 ml of THF, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [O:1]=[O+][O-].[Br:4][C:5]1[C:13]2[O:12]C(C)=[CH:10][C:9]=2[C:8]([F:15])=[CH:7][CH:6]=1.CSC>>[Br:4][C:5]1[C:13]([OH:12])=[C:9]([C:8]([F:15])=[CH:7][CH:6]=1)[CH:10]=[O:1]
Reactant: O=[O+][O-]
Reactant: Cc1cc2c(F)ccc(Br)c2o1
Solvent: CSC
Product: O=Cc1c(F)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Ozone was conducted into a solution of 8.0 g (35 mmol) of 7-bromo-4-fluoro-2-methylbenzofuran at -78° C. until the colour became blue. Subsequently, argon was conducted through the solution which was then treated at -78° C. with 13 ml of dimethyl sulfide. After warming to room temperature the solution was concentrated in a vacuum and the residue was dissolved in 50 ml of ethanol. After the addition of 50 ml of 3% sodium hydrogen carbonate solution the mixture was stirred at 70° for 30 minutes. Subsequently, the mixture was poured on to 200 ml of ice-water, made acid with 10% HCl and extracted three times with 150 ml of diethyl ether. After drying over sodium sulfate concentration was carried out in a vacuum. The crude product obtained was purified by column chromatography on silica gel (dichloromethane/hexane 4:1). There were obtained 7.5 g (98%) of 3-bromo-6-fluoro-2-hydroxy-benzaldehyde as a pale yellow oil, which was used immediately in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24](Cl)[N:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:21][C:22]1[N:23]=[C:24]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:25]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:27]=1
Reactant: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(Cl)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g (3.2 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.94 g (3.4 mmol) (2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT. Then the reaction mixture was evaporated down, the residue was mixed with water and stirred for 30 min at RT. The precipitated solid was suction filtered, stirred with diisopropylether and isopropanol and suction filtered again. After drying the crude product was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1)[CH3:5].[H][H].CS([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)(=O)=O>CN(C=O)C.O>[CH3:5][C:4]([CH3:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:9][CH:8]=1)[CH3:3]
Reactant: CC(C)(C)Oc1ccc(CCO)cc1
Reactant: [H][H]
Reactant: CS(=O)(=O)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(CCOc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a suspension of about one-half gram of 60% NaH (dispersion in oil) in 10 mL of dry DMF was added 1.5 g (0.0077 m) of 2-[4-(1,1-dimethylethoxy)phenyl]ethanol. The mixture was stirred in a warm water bath until hydrogen evolution ceased. After 30-40 minutes, 1 g (0.0064 m) of 4-(methylsulfonyl)pyridine in 5-7 mL of DMF was added. The mixture was stirred at room temperature overnight, then diluted with water. The product was extracted into CH2Cl2, and the extracts were washed with saturated brine, filtered through phase separating paper, and concentrated in vacuo. The resulting material was azeotroped with xylene to remove excess DMF. This material was adsorbed onto silica gel and chromatographed over silica gel 60 (230-400 mesh) using CH2Cl2 →50% EtOAc/CH2Cl2 to give the title product as an oil. Yield 0.7 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2.[CH3:18][S:19](Cl)(=[O:21])=[O:20].CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1.[Cl-].[Na+]>CN(C)C=O.N1C=CC=CC=1>[CH3:18][S:19]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](=[O:16])[CH2:13][CH2:14][Cl:15])[NH:8][C:7](=[O:17])[CH2:6][CH2:5]2)(=[O:21])=[O:20]
Reactant: O=C1CCc2cc(O)c(C(=O)CCCl)cc2N1
Reactant: CS(=O)(=O)Cl
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCCl)NC(=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.06 Grams of 6-hydroxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril and 1.8 g of anhydrous pyridine were mixed with 50 ml of dimethylformamide. Then the mixture was cooled with ice and 2.5 g of methanesulfonyl chloride was added to the mixture and stirred at a room temperature for 3 hours. The reactin mixture was poured into 100 ml of a saturated sodium chloride solution and extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation under a reduced pressure to obtain a residue. The residue was crystallized by adding 80 ml of hexane to obtain crude crystals. The crude materials were collected by filtration and were recrystallized from ethanol to obtain 4.5 g of 6-methylsulfonyloxy-7-(3-chloropropionyl)-3,4-dihydrocarbostyril in white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.CC(=[N:11][OH:12])C.F[C:14]1[C:39]([C:40]#[N:41])=[CH:38][CH:37]=[CH:36][C:15]=1[C:16]([NH:18][C:19]1[C:20]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:17]>CN(C=O)C>[NH2:41][C:40]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:15]([C:16]([NH:18][C:19]3[C:20]([NH:25][C:26](=[O:35])[C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:17])[C:14]=2[O:12][N:11]=1
Reactant: CC(C)=NO
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2cccc3c(N)noc23)cc1
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a suspension of potassium t-butoxide (92 mg, 0.82 mmol) in DMF (5 mL) was added acetone oxime hydrochloride (60 mg, 0.82 mmol). After 1 h, N1-(2-fluoro-3-cyanobenzoyl)-N2-(4-methoxybenzoyl)-1,2-benzenediamine (290 mg, 0.74 mmol) was added. After another 2 h, potassium t-butoxide (92 mg, 0.82 mmol) and acetone oxime hydrochloride (60 mg, 0.82 mmol) were added. After 12 h, the reaction was concentrated and the residue was dissolved in ethyl acetate and washed with water (2×), brine, MgSO4 dried, and concentrated. The resulting solid was dissolved in ethanol (35 mL), 5% HCl (35 mL) was added, and the mixture was refluxed for 1 h. The reaction was cooled, concentrated to 2 mL, diluted with ethyl acetate (250 mL), and neutralized with satd aq NaHCO3. The organic layer was washed with satd aq NaHCO3 (2×) and brine, MgSO4 dried, concentrated and crystallized to give the title compound as an off-white solid (106 mg, 35%); MS(FD): 402.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(#N)C.ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNS(=O)(=O)c1ccc(F)cc1
Temperature: 4 °C
Yield: 40.9 %

Procedure:
1-(4-Aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) was dissolved in anhydrous acetonitrile (35 mL) and the solution was cooled to 4° C. A solution of 4-fluorobenzenesulfonyl chloride (0.194 g, 1.0 mmol) in anhydrous dichloromethane (10 mL) was slowly added. The reaction was allowed to slowly warm to ambient temperature over the weekend. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The layers were separated and the organic layer was concentrated to provide a pale yellow solid. This material was recrystallized from isopropyl alcohol and then further purified by flash chromatography (silica gel eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated. The residue was recrystallized from isopropyl alcohol to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-fluoro-1-benzenesulfonamide as a pale yellow solid, m.p. 214–216° C. Analysis: Calculated for C26H24FN5O2S: % C, 63.79; % H, 4.94; % N, 14.30; Found: % C, 63.19; % H, 4.85; % N, 13.90. Mass spec M+1=490.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1(B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1>C(COC)OC.O>[C:16]1([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[CH:3][C:2]=2[F:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: Nc1ccc(I)c(F)c1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Nc1ccc(C2=CCCCC2)c(F)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
In a pressure tube, a solution of 3-fluoro-4-iodoaniline (2.29 g, 9.66 mmol) and potassium carbonate (1.74 g, 12.58 mmol) in 4:1 dimethoxyethane-water (33 mL) was degassed by nitrogen sparge for 40 minutes, followed by addition of 1-cyclohexenyl boronic acid pinacol ester (2.7 mL, 2.61 g, 12.56 mmol). Then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane complex (237 mg, 0.29 mmol) was added followed by degassing for another 5 minutes. The pressure tube was sealed and warmed at 100° C. for 18 hours. The mixture was cooled and diluted with ethyl acetate, followed by extraction with water and saturated sodium chloride solution. The solution was dried (Na2SO4) and stirred with 3-(mercaptopropyl) silica gel for 1 hour. Concentration in vacuo afforded a brown oil, which was chromatographed over a 340 g silica gel cartridge, eluting with 10-100% ethyl acetate in hexanes. These procedures afforded the title compound (1.16 g, 63%) as a light brown oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.00 (m, 1 H), 6.37 (m, 2 H), 5.84 (s, 1 H), 3.71 (br s, 2 H), 2.32 (m, 2 H), 2.17 (m, 2 H), 1.73 (m, 2 H), 1.65 (m, 2 H); MS (+DCI) m/z (rel abundance) 192 (100, M+H).
Reaction SMILES: [NH:1]([C:21]([O:23]C(C)(C)C)=O)[C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])=[O:5])[CH3:3].[NH:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29]C(O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>Cl.O1CCOCC1.CN(C=O)C>[NH:28]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][C:21]([NH:1][C@H:2]([C:4]([N:6]1[CH2:20][CH2:19][CH2:18][C@H:7]1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:5])[CH3:3])=[O:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
Boc-Ala-Pro-OBzl (75.3 g, 0.2 mole) was deprotected by stirring for 1.5 h. in 4.2N HCl in dioxane. Excess HCl and dioxane were removed under reduced pressure, triturated with ether, faltered, washed with ether, and dried (yield 100%). A solution of Boc-Gly-OH (35.04 g, 0.2 mole) and HOBt (27.02 g, 0.2 mole) in DMF was cooled to -15° C. with stirring and EDCI (38.34 g, 0.2 mole) was added. After 20 min, a pre-cooled solution containing the above hydrochloride salt and NMM (21.98 mL, 0.2 mole) was added and the reaction mixture was stirred overnight at room temperature. The mixture was evaporated to a thick oil which was dissolved in CHCl3. This solution was extracted with water, 10% citric acid, water, 5% NaHCO3, water, and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting oil was crystallized from ether/petroleum ether. The solid was faltered, washed with petroleum ether, and dried to obtain 76.2 g (yield 87.88%) of II. Rf1 0.39; Rf2, 0.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([CH:11]=[O:12])=[C:4]2[CH:3]=1.C([Mg]Br)#C.O.O1C[CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:10]([C:11](=[O:12])[C:26]#[C:27][CH3:28])=[C:4]2[CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Agent: C#C[Mg]Br
Solvent: O
Product: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine-3-carbaldehyde (0.93 g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added ethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Water was added to the reaction and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid residue. This residue was dissolved in dichloromethane (50 mL) and manganese dioxide (5 g) was added. This slurry was stirred at room temperature for 2 hours. The manganese dioxide was removed by filtration and the filtrate was concentrated to a solid. This solid was purified by flash chromatography (dichloromethane) to give 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (0.63 g, 62% for two steps) as a white solid. 1H-NMR (CDCl3): δ 8.52 (d, 1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s, 1H); 19F-NMR (CDCl3): δ −111.69; MS m/z 299 (M+1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH2:12][CH2:13]C#N)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].[I:16]C[CH2:18][O:19]C>C(#N)C>[I-:16].[C:1]([CH2:3][CH2:4][PH+:5]([CH2:12][CH2:13][O:19][CH3:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2]
Reactant: N#CCCP(CCC#N)c1ccccc1
Reactant: COCCI
Solvent: CC#N
Product: COCC[PH+](CCC#N)c1ccccc1
Product: [I-]

Procedure:
8.5 g (0.04 mole) of bis-(β-cyanoethyl)-phenylphosphine are dissolved in 50 ml of absolute acetonitrile in a nitrogen atmosphere. Then 7.71 g (0.04 mole) of 1-iodo-2-methoxyethane are added and the mixture is refluxed for 12 hours. The solvent is distilled off to yield 13.2 g (82% of theory) of the product in the form of a solid, glassy substance.
Reaction SMILES: [CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1>>[CH:1]1([N:4]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=S(=O)(c1ccccc1)N(C1CCNCC1)C1CC1
Product: CC(C)(C)c1ccc(CN2CCC(N(C3CC3)S(=O)(=O)c3ccccc3)CC2)cc1

Procedure:
Also, N-cyclopropyl-N-[1-(4-tert-butylbenzyl)piperidin-4-yl]-benzenesulfonamide was prepared from N-cyclopropyl-N-piperidin-4-yl-benzenesulfonamide and 1-bromomethyl-4-tert-butylbenzene. LC: 100%, MS: m/z=427.2, 428.3 (M+H+). 1H NMR (400 MHz, CDCl3): δ 7.85 (2H, m), 7.56 (1H, m), 7.50 (2H, m), 7.32 (2H, d, J=8.4 Hz), 7.19 (2H, d, J=8.4 Hz), 3.85 (1H, m), 3.44 (2H, s), 2.89 (1H, s), 2.87 (1H, s), 1.97 (5H, m), 1.59 (4H, s), 1.49 (1H, s), 1.47 (1H, s), 1.32 (9H, s), 0.97 (2H, m), 0.75 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[Cl:21][CH2:22][CH2:23][CH2:24][C:25]([NH:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[F:1])=[O:26]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCCCl)Nc1cc([N+](=O)[O-])ccc1F
Reaction time: 2 h

Procedure:
2-Fluoro-5-nitroaniline (500 mg, 3.2 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) were stirred in dry dichloromethane (10 ml) under nitrogen. 4-Chlorobutyryl chloride was added drop-wise over 1 minute and the reaction was stirred for a further 2 hrs. The reaction mixture was partitioned between water (50 ml) and dichloromethane (50 ml). The organics were collected, dried (magnesium sulphate), concentrated in vacuo and the residue purified by flash column chromatography (SiO2) eluting with dichloromethane to give 537 mg of 4-chloro-N-(2-fluoro-5-nitro-phenyl)-butyramide as a white solid. This material was re-dissolved in dry tetrahydrofuran and cooled over an ice-bath. Sodium hydride (83 mg, 2 mmol) was added and the reaction was stirred at room temperature for 3 hr. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (50 ml). The organics were washed with water (50 ml), dried (magnesium sulphate) and concentrated in vacuo to give 430 mg of crude 1-(2-fluoro-5-nitro-phenyl)-pyrrolidin-2-one as a yellow solid. This material was suspended in diethyl ether (20 ml) and ethanol (2 ml). A solution of tin (II) chloride dihydrate in concentrated HCl (20 ml) was added drop-wise over 5 minutes and the reaction stirred at room temperature for 3 hrs. The reaction mixture was neutralised to pH 7 by addition of 2M sodium hydroxide (aq) and the resulting solution was extracted with dichloromethane (2×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford crude 1-(5-amino-2-fluoro-phenyl)-pyrrolidin-2-one (424 mg, 68%) as a yellow solid. HPLC retention time 3.3 min. Mass spectrum (ES+) m/z 195 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]1=[S:21].[N:22]1([C:31]([N:33]2[CH2:36][C:35]([F:38])([F:37])[CH2:34]2)=N)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C.O1CCOCC1>[F:37][C:35]1([F:38])[CH2:36][N:33]([C:31](=[NH:22])[NH:1][CH2:2][CH2:3][CH2:4][N:5]2[C:10]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[O:18][CH3:19])=[CH:9][C:8](=[O:20])[NH:7][C:6]2=[S:21])[CH2:34]1
Reactant: COc1ccc(F)cc1-c1cc(=O)[nH]c(=S)n1CCCN
Reactant: N=C(N1CC(F)(F)C1)n1nnc2ccccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1cc(=O)[nH]c(=S)n1CCCNC(=N)N1CC(F)(F)C1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a mixture of 1-(3-aminopropyl)-6-(5-fluoro-2-methoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (prepared in an analogous manner to Example 6; 50 mg, 0.14 mmol) and 1-(1H-benzotriazol-1-yl)-1-(3,3-difluoroazetidin-1-yl)methanimine (47.5 mg, 0.174 mmol) in DMF (0.46 mL) was added N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) under nitrogen and heated at 60° C. under nitrogen for 1 h. The reaction mixture was cooled to room temperature, and treated with 4N HCl in dioxane (0.25 mL). The mixture was stirred at room temperature for 10 min, then concentrated in vacuo and azeotroped with heptanes (3×10 mL). The residue was dissolved in water (1 mL) and purified using medium pressure reverse-phase (C18) chromatography (100:0 to 70:30 water/acetonitrile) to give the title compound as a white solid (22 mg, 33%).