Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C@H:3]1[C:8](=[O:9])[N:7]([CH2:20][CH3:21])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:5]=2[O:4]1)[CH3:2]
Reactant: CCI
Reactant: CC[C@@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1Oc2cc(C(=O)OC)ccc2N(CC)C1=O
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (S)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 14(2)] (2.00 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.37 g) and ethyl iodide (1.90 g) and the mixture was stirred under ice cooling for 2 hours. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give (S)-2,4-diethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.15 g).
Reaction SMILES: C(O)(=O)C.CC1(C)CO[CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21]([CH2:22][C@@H:23]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:24][C@@H:25]3[O:33][CH2:34][O:35][CH3:36])=[CH:20][CH:19]=4)[CH2:16][CH2:15]2)[CH3:13])[O:8]C1>O1CCCC1>[Si:38]([O:37][C@H:23]1[CH2:24][C@H:25]([O:33][CH2:34][O:35][CH3:36])[C@@:26]2([CH3:27])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:31]2([CH3:32])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[CH:12]([CH:9]=[O:8])[CH3:13])[CH2:22]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40]
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 5 ml of tetrahydrofuran was dissolved 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene, followed by addition of 5 ml of 80% acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 50 mg of 3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7 -diene-20-carbaldehyde showing the following physical properties. 1H-NMR spectrum (90 MHz) δTMSCDCl 3: 0.13 (s, 6H), 0.66 (s, 3H), 0.95 (s, 9H), 1.01 (s, 3H), 1.14 (d, J=6.2 Hz, 3H), 3.40 (s, 3H), 4.10-4.50 (2H), 4.80 (br. s, 2H), 5.35 (m, 1H), 5.70 (m, 1H), 9.59 (d, J=3.5 Hz, 1H) IR spectrum (KBr): 1725 cm-1
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([SiH:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1.C(OCC)(=O)C>C1COCC1.ClCCl>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([SiH:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc([SiH](C(C)C)C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)[SiH](c1ccc(CO)cc1)C(C)C
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
LiAlH4 (1.2 g, 32 mmol) was dissolved in anhydrous THF (80 mL), and to this was slowly added dropwise the anhydrous THF solution (80 mL) 4-diisopropylsilanylbenzoic acid methyl ester (2) (8 g, 32 mmol). The resulting mixture was then stirred for 10 min and ethyl acetate (20 mL) was added slowly to it. The reaction mixture was diluted with dichloromethane (500 mL), and then extracted three times with 0.2 N hydrochloric acid aqueous solution (400 mL). An organic layer was collected and dehydrated with anhydrous sodium sulfate and filtered so that the resulting solvent was distilled out under a reduced pressure to give a desired product (7.2 g, quant). Its NMR data are as follows:
Reaction SMILES: [CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[NH:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)=[O:32])[N:26]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:52](Cl)CCl.CO>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:1]1([O:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:51])[C@@H:15]([NH:21][C:22]([C:24]3[CH:28]=[C:27]([O:29][CH2:30][C:31]([N:33]4[CH2:37][CH2:36][CH2:35][C@H:34]4[C:38](=[O:44])[NH:39][CH:40]4[CH2:43][CH2:42][CH2:41]4)=[O:32])[N:26]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:25]=3)=[O:23])[CH2:16][CH2:17][C:18]([O:20][CH3:52])=[O:19])[CH2:10][CH2:9]2)=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: ClCCCl
Reactant: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)OC2CCC2)CC1

Procedure:
To a solution of 150 mg 4-[(S)-4-Carboxy-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-butyryl]-piperazine-1-carboxylic acid cyclobutyl ester in 3 ml DMF were added 42 mg EDC, 27 mg DMAP and 37 μl methanol. After 3 h the reaction mixture was concentrated and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 45 mg MS (ES+): m/e=722.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1C=CC=CC=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])=[CH:15][CH:14]=1.[CH3:25][N:26](C)C1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[NH2:26][CH2:25][C@@H:5]1[O:4][C:2](=[O:3])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[CH:15][CH:14]=2)[CH2:6]1
Reactant: Nc1ccc(N2CCCC2=O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC[C@H]1CN(c2ccc(N3CCCC3=O)cc2)C(=O)O1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
At −20° C., benzyl chloroformate (4.27 g, 25.03 mmol) is slowly added dropwise to 1-(4-aminophenyl)pyrrolidin-2-one (4 g, 22.7 mmol) and N,N-dimethylaniline (3.6 ml, 28.4 mmol) in tetrahydrofuran (107 ml). The reaction mixture is stirred at −20° C. for 30 min and then warmed to room temperature. After addition of ethyl acetate (0.5 l), the organic phase is washed with saturated NaCl solution (0.5 l). The combined organic phase are dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue is titrated with diethyl ether and filtered off with suction. Yield: 5.2 g, 74% of theory, light-beige crystals, melting point: 174° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[CH3:40][O:39][C:37](=[O:38])[NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:23](=[O:25])[CH3:24])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:34][CH:35]=1
Reactant: COC(=O)Cl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN)cc2)c2ccccc21
Solvent: ClCCl
Product: COC(=O)NCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
(2S,4R)-N-{1-[4-(3-Amino-propoxy)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-(4-chloro-phenyl)-acetamide (150 mg, 0.30 mmol) was dissolved in DCM (1 mL). To this solution was added TEA (36.4 mg, 0.36 mmol) followed by methyl chloroformate (34 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and dissolved in DCM (15 mL). The reaction mixture was washed with sat. aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5/95 ethyl acetate/hexane-50/50 ethyl acetate/hexane gradient) to afford white solid product (71 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([C:16]([O:18]C)=O)[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1.[NH3:20]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH:11]([C:16]([NH2:20])=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][C:5]2=1
Reactant: N
Reactant: COC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Solvent: CO
Product: NC(=O)C1CCCCc2c1[nH]c1ccc(Cl)cc21
Temperature: 90 °C
Yield: 21 %

Procedure:
Methyl 2-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-6-carboxylate (10 g, 36 mmol) was dissolved in 7 N ammonia in methanol (350 mL) and transferred to Parr pressure reactor. The reaction vessel was purged briefly to displace any air with Nitrogen. The reaction was then heated to 90° C. for 48 h. The reaction was cooled to r.t. and the solvent removed in vacuo, the crude residue was applied to a Biotage and eluted with grading (1/1 heptane/ethyl acetate to 0/1 heptane/ethyl acetate) to afford product as an off white foam, which was triturated with DCM to afford pure product 2 g (21%) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[CH2:13][CH3:14].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:12]([CH2:13][CH3:14])[CH2:9][C:8]2=[O:10]
Reactant: CCC=O
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCC1CC(=O)c2cc(Br)ccc2O1
Temperature: 60 °C
Yield: 33 %

Procedure:
The mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (10 g, 46.50 mmol), propionaldehyde (6.7 mL, 93 mmol), pyrrolidine (3.9 mL, 47 mmol), and acetic acid (3.2 mL, 56 mmol) in toluene (20 mL) was heated to 60° C. for 18 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The mixture was diluted with diethyl ether and 1M aqueous HCl. The phases were separated. The organic phase was washed with 1M aqueous NaOH, then brine. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification with silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 1 to 10%) afforded 6-bromo-2-ethyl-2,3-dihydro-4H-chromen-4-one (3.92 g).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.P(=O)(O)(O)O>C1(C)C=CC=CC=1>[Br-:23].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][P+:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:26][CH:25]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([P+](Cc2ccc(Br)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Product: [Br-]
Temperature: 30 °C

Procedure:
Into a 50 milliliter glass reactor equipped with a thermometer connected to a temperature controller, a heating mantle, a condenser and a magnetic stirring bar, is charged 5.04 gms (0.0166 mole) of tri-p-tolyl phosphine and 25 gms of toluene. The slurry is heated to 30° C. then 4.6 gms (0.0184 mole) of 4-bromobenzyl bromide is added. This reaction mass is heated to 100° C. and maintained at that temperature for 3.5 hours, then cooled to 29° C. and the resulting phosphonium salt collected by filtration. The salt is washed with 12 gms of toluene then vacuum dried. There is obtained 7.5 gms of catalyst which has a melting point of >250° C. and a chemical shift of 22.1 ppm (phosphoric acid reference).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([Cl:23])[CH:17]=1.[OH-].[Na+]>CN(C=O)C>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)[CH:21]=[C:20]([Cl:22])[N:19]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc(Nc2ncnc3[se]c4c(c23)CCCC4)cc(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (470 mg, 1.72 mmol, from step b of example 1) in DMF (10 mL) was added sequentially 4-amino-2,6-dichloropyridine (420 mg, 2.58 mmol) and powdered NaOH (210 mg, 5.16 mmol) at rt and the mixture was stirred at rt for 16 h. Work-up of the mixture as described in example 2, gave the product as a pale yellow color solid (500 mg, 73%), mp 238-242° C. 1H NMR (400 MHz, DMSO-d6): δ 9.00 (1H, s, exchangeable with D2O), 8.62 (1H, s), 7.76 (2H, s), 3.07 (2H, br s), 2.94 (2H, br s), 1.84 (4H, br s); 13C NMR (100 MHz, DMSO-d6): δ 172.3, 153.1, 151.3, 151.0, 149.2, 140.5, 128.3, 122.3, 112.1, 27.7, 26.7, 22.6, 21.9; LC-MS (negative ion mode): m/z 395, 397, 399 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>O1CCOCC1.C(Cl)Cl.O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:30][C:26]([CH3:27])([CH3:25])[C:28]#[C:29][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(Br)cnc21
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)C#Cc1cnc2c(c1)c1cc(C#N)ncc1n2COCC[Si](C)(C)C
Temperature: 105 °C
Yield: 124.2 %

Procedure:
In a flame dried flask, a mixture of 3-bromo-9-(2-trimethylsilanylethoxymethyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (203 mg, 0.503 mmol) and copper (I) iodide (9.58 mg, 50.3 μmol) in 1,4-dioxane (5.3 mL) was degassed and flushed with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (58.1 mg, 50.3 μmol) and 2-methyl-3-butyn-2-ol (244 μL, 2.52 mmol) were added and the reaction mixture was degassed, purged with nitrogen, and heated at 105° C. for 70 min. The cooled reaction mixture was diluted with DCM and water, the layers separated, and the aqueous phase extracted into DCM. The combined organic phase was dried over sodium sulfate and concentrated in vacuo. The resultant residue was dissolved in EtOAc and absorbed onto silica gel for purification by flash chromatography (silica, 25 g column, Biotage, 1-100% EtOAc in heptane) to afford further title compound as a white-yellow solid (254 mg, 124%). The solid was used without further purification. 1H NMR (DMSO-D6, 400 MHz): 9.33 (s, 1H), 8.98 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 6.03 (s, 2H), 5.55 (s, 1H), 3.57 (t, J=7.9 Hz, 2H), 1.51 (s, 6H), 0.82 (t, J=8.0 Hz, 2H), −0.16 (s, 9H).
Reaction SMILES: [CH2:1]([C:8]([CH3:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](Cl)[CH:12]=[CH:13][CH3:14].ClC(C)C=C>>[C:2]1([CH:1]([C:8](=[O:9])[CH3:10])[CH2:11][CH:12]=[CH:13][CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: CC=CCCl
Agent: C=CC(C)Cl
Product: CC=CCC(C(C)=O)c1ccccc1

Procedure:
Methyl benzyl ketone is reacted with crotyl chloride or 3-chloro-1-butene in accordance with the foregoing details and there is obtained 5-phenyl-hept-2-en-6-one of boiling point 88° C./3 mmHg; nD20 =1.5190. When 3-chloro-1-butene is used there is also obtained 3-methyl-5-phenyl-hex-1-en-5-one which is separated by distillation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.O1CCOCC1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)CC)C>[C:30]([O:8][C:5]1[CH:4]=[C:3]([O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Oc1cc(=O)[nH]cc1Cl)c1cccnc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(Oc1cc(OC(=O)c2cccnc2)c(Cl)cn1)c1ccccc1
Yield: 54 %

Procedure:
A 300 ml quantity of 5-chloro-4-nicotinoyloxy-2-pyridone was suspended in a mixture solvent of 30 ml of dioxane and 10 ml of pyridine and to the suspension were added 0.17 ml of benzoyl chloride and 0.83 ml of triethylamine. The mixture was refluxed for 3 hours. The resulting reaction mixture was concentrated and the concentrate was subjected to silica gel column chromatography using as an eluent, chloroform, thereby producing 230 mg of the title compound in a yield of 54%.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[F:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C>[CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([NH:23][C:24]2[CH:25]=[C:26]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]5[CH2:42][CH:41]5[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH:44]=[CH:45][C:46]=2[F:47])=[O:10])[N:5]([CH3:11])[N:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: CC1CC1C(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2F)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (158 mg, 1.03 mmol) in tetrahydrofuran (3.8 mL) were added N,N-dimethylformamide (20 μL, 0.26 mmol) and oxalyl chloride (90 μL, 1.03 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to a solution of N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (250 mg, 0.73 mmol) in N,N-dimethylacetamide (5.0 mL), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate alone) and recrystallized from hexane/ethyl acetate to give the title compound (201 mg, 57%) as a white powder.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]2=[O:19])(=[O:5])[CH3:4]>CO>[Br:1][CH2:4][C:3]([C:6]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]2=[O:19])=[O:5]
Reactant: BrBr
Reactant: CC(=O)C12CCCCC1c1ccccc1C2=O
Solvent: CO
Product: O=C(CBr)C12CCCCC1c1ccccc1C2=O
Reaction time: 2 h

Procedure:
Bromine (1.2 ml) was added to a mixture of 9a-acetyl-1,2,3,4,4a,9a-hexahydrofluoren-9-one (5 g) in methanol (20 ml) at 20-30° C. The reaction mixture was stirred for 2 hours and quenched with NaHCO3 solution (0.8 g NaHCO3 and 24 ml water). The mixture was extracted with CH2Cl2 (3×30 ml) and the organic phase was washed with water (30 ml) and dried over Na2SO4. Evaporation gave 6.6 g of the crude product which was used without further purification for the next step.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:7]=2[CH:6]=1)=[O:4].[OH:17][CH:18]([CH2:21][OH:22])[CH2:19][NH2:20]>CO>[OH:17][CH:18]([CH2:21][OH:22])[CH2:19][NH:20][C:3]([C:5]1[S:9][C:8]2[S:10][C:11]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Reactant: NCC(O)CO
Solvent: CO
Product: NS(=O)(=O)c1cc2cc(C(=O)NCC(O)CO)sc2s1
Yield: 72.3 %

Procedure:
5-Methoxycarbonylthieno[2,3-b]thiophene-2-sulfonamide (0.83 g., 3 mmoles) and 2,3-dihydroxypropylamine (1.37 g., 15 mmoles) were dissolved in hot methanol and refluxed for 48 hours. The reaction was worked up by evaporating the methanol in vacuo. Water (7 mL) was added followed by the dropwise addition of conc. HCl until strongly acidic (~1.8 pH). The product crystallized out and was collected, washed with water and dried to give 0.90 g of crude product. Recrystallization from nitromethane gave 0.73 g of 5-(N-2,3-dihydroxypropylcarbamoyl)thieno[2,3-b]thiophene-2-sulfonamide, m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[C:8]#[N:9])(=[O:5])=[O:4])[CH3:2].F[C:18]1C=CC([N+]([O-])=O)=CC=1C#N.CC(S)C.C1C=C(Cl)C=C(C(OO)=O)C=1>>[CH:1]([S:3]([C:6]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:7]=1[C:8]#[N:9])(=[O:4])=[O:5])([CH3:18])[CH3:2]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Agent: CC(C)S
Agent: O=C(OO)c1cccc(Cl)c1
Product: CC(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C#N
Yield: 91 %

Procedure:
Using a procedure analogous to that used to prepare 6A, 2-fluoro-5-nitrobenzonitrile (2.50 g, 15.6 mmol) was reacted with isopropylthiol and oxidized with mCPBA to afford 9A (3.04 g, 91%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.40 (d, J=7.03 Hz, 6 H), 3.55-3.76 (m, 1 H), 8.38 (d, J=8.35 Hz, 1 H), 8.63 (dd, J=8.79, 2.20 Hz, 1 H), 8.74 (d, J=2.64 Hz, 1 H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14](O)=[O:15])=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3].[CH3:28][NH:29][CH3:30].CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][C:14]([N:29]([CH3:30])[CH3:28])=[O:15])=[C:7]([N+:25]([O-:27])=[O:26])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]

Procedure:
A solution of Example 122E (411 mg, 1 mmol), 2M dimethylamine in THF (1 mL), EDCI (296 mg, 1.5 mmol), and DMAP (10 mg) in DMF (10 mL) at room temperature was stirred for 16 hours, diluted with ethyl acetate (200 mL), washed sequentially with 1N HCl (50 mL), water (50 mL), and brine (20 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide the desired product. MS (ESI(+)) m/e 439 (M+H)+.