Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S[CH2:8][N:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[NH:11][S:10]2(=[O:19])=[O:18])C=CC=CC=1.S(Cl)([Cl:23])(=O)=O>C(Cl)Cl>[Cl:23][CH2:8][N:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH2:16][CH3:17])[NH:11][S:10]1(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCC1NS(=O)(=O)N(CSc2ccccc2)C1=O
Solvent: ClCCl
Product: CCCC1NS(=O)(=O)N(CCl)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 2-phenylthiomethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (1.1 g, 3.6 mmol) in 10 ml of methylene chloride was added sulfuryl chloride (0.44 ml, 5.5 mmol) and the mixture was stirred for 3 hours at room temperature. The mixture was concentrated in vacuo, the residue triturated in hexane (50ml) for 1 hour, the resulting solid filtered and purified by silica gel flash column chromatography (20-25% of ethyl acetate in hexane) to afford 0.31 g of 2-chloromethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula II: R1 =H; R2 =propyl; R3 =H; X'=Cl) as a solid, m.p. 62°-63.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH:13]3[CH2:14][CH2:15][N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11][CH2:12]3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCN(c4ccc(F)cc4)CC3)CC2)cc1

Procedure:
3.0 g (13.6 mmol) of 1-(4-nitrophenyl)-4-piperidone [cf. Taylor et al., Synthesis (1981) 606], 2.5 g (13.6 mmol) of N-(4-fluorophenyl)piperazine, 0.8 g (13.6 mmol) of acetic acid and 0.9 g (13.6 mmol) of sodium cyanoborohydride were reacted as in Example 1.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:1]([NH:8][C@@H:9]([C:11]([NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:13])[CH3:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)CNC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: -70 °C

Procedure:
18.9 Grams of Boc-D-alanine are dissolved in 100 ml of methylene chloride, and 22.0 ml of N-methylmorpholine is added. The solution is cooled to -70° C. and 13.0 ml of isobutylchloroformate is added. The reaction mixture is warmed to -15° C. and again cooled to -70° C. and 12.6 g of methyl glycinate hydrochloride is added. The reaction mixture is stirred for sixteen hours at room temperature then extracted three times with a 1.0 M solution of potassium bisulfate, saturated potassium bicarbonate solution, and a saturated sodium chloride solution. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The product is purified by chromatography on silica gel using methanol-chloroform eluant. Removal of the solvent provides methyl Boc-D-alanylglycinate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:11]=3[N:22]([CH3:32])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])=[N:4]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:11]=3[N:22]([CH3:32])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:25])=[N:4]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](COS(C)(=O)=O)CS3)cc2c1
Yield: 76.7 %

Procedure:
A solution of N-[2-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (0.28 g), methanesulfonyl chloride (0.10 g) and triethylamine (0.16 mL) in tetrahydrofuran (5.0 mL) was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.25 g, yield 77%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.II>C(O)(=O)C.O>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH2:10])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C(C)(O)c2cccc(OC)c2)c1
Agent: II
Solvent: CC(=O)O
Solvent: O
Product: C=C(c1cccc(OC)c1)c1cccc(OC)c1
Yield: 96.3 %

Procedure:
5.28 g (20 mmoles) of 1,1-bis(3-methoxyphenyl)ethanol are dissolved in 30 mL of glacial acetic acid. A catalytical amount of iodine is added and the solution refluxed for about 5-15 minutes or until the dehydration is complete. The progress of the reaction is monitored by TLC on silica (5% EtOAc in hexanes). The burgundy red solution is diluted with water (100 mL) and the product extracted with ether (2-3 extractions with 10 mL portions). The combined ethereal extracts are washed consecutively with water (into which a spatula tip of sodium metabisulfite was added) and 10% sodium carbonate, dried over anh. K2CO3 and evaporated to yield 4.63 g (96%) of the title compound. 1H NMR (CDCl3): 6.8-7.3 (m, ArH, 8H), 5.45(s, C═CH2, 2H), 3.75 (s, OCH3, 6H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([C:27]1N=C(N2CCC(F)(F)C2)[C:30]2N=[N:34][NH:33][C:31]=2[N:32]=1)(C)(C)C.ClCC1N(C)C(C)=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:32]([CH3:27])[C:31]([CH3:30])=[N:33][N:34]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cc1nnc(CCl)n1C
Product: Cc1nnc(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole and isolated as light-yellow solid. MS (m/e): 392.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:48][CH2:49][C:50](O)=[O:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:44]([O:43][C:41]([NH:48][CH2:49][C:50]([O:33][C@@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:51])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
To a mixture of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.0 g, 1.84 mmol), N-Boc-glycine (0.644 g, 3.68 mmol, ABCR) and DMAP (0.45 g, 3.68 mmol, Aladdin) in 12 mL of CH2Cl2 at 0° C. was added EDC solid (1.0582 g, 5.52 mmol, Aladdin) in portions. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature and continued to stir overnight. The reaction mixture was diluted with CH2Cl2 (100 mL), and the result solution was washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 (10 mL×2) and water (20 mL), the aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc:hexane=2:1) to give the desired compound as a yellow solid (1.46 g, 70.1%).
Reaction SMILES: [N+]([O-])(O)=O.[I:5]I.[CH:7]1([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH2:9][CH2:8]1>O>[CH:7]1([C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[I:5])[CH2:9][CH2:8]1
Reactant: II
Reactant: Cc1cc(C2CC2)on1
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1noc(C2CC2)c1I
Yield: 109.6 %

Procedure:
Concentrated nitric acid (10 ml) was added dropwise to a stirred heated mixture of iodine (23.8 g) and 5-cyclopropyl-3-methylisoxazole (24.6 g coming approximately 20% 3-cyclopropyl-5-methylisoxazole) whilst maintaining the temperature in the range 90°-95° C. The mixture was stirred and heated at 95°-100° C. for 1 hour. It was cooled, poured into cold water and extracted with ether. The combined extracts were washed with aqueous sodium bicarbonate solution (saturated), aqueous sodium metabisulphate solution (saturated), water, dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated to dryness and the residue was triturated with petroleum spirit and filtered. The solid was recrystallized from petroleum spirit to give 5-cyclopropyl-4-iodo-3-methylisoxazole (25.6 g) as a white solid, m.p. 71° C.
Reaction SMILES: [Na].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([OH:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][N:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[CH2:26]([O:25][C:23]([N:22]([CH2:28][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])[CH3:21])=[O:24])[CH3:27]
Reactant: CCOC(=O)N(C)CCl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)COC(=O)C1=C(COC(C)=O)CSC2C(N)C(=O)N12
Temperature: 0 °C

Procedure:
725 mg (2.5 mM) of the sodium salt of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid in 50 of dimethyl formamide is treated at room temperature with 375 mg (2.5 mM) of N-chloromethyl-N-methylurethane for one hour. The mixture is carefully poured into ice water and the precipitated solid is removed by filtration and washed with water. The solid is dissolved in ethylacetate and washed with aqueous sodium bicarbonate and then with water. The organic layer is dried over magnesium sulfate filtered and evaporated to dryness in vacuo to give 3-[(acetyloxy)methyl]-7-amino-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-ethoxycarbonyl-N-methylaminomethyl ester.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH2:33][CH2:34][CH2:35][N:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[NH:38][C:37]1=[O:45].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([N:7]2[C:11]3([CH2:16][CH2:15][N:14]([CH2:33][CH2:34][CH2:35][N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[NH:38][C:37]4=[O:45])[CH2:13][CH2:12]3)[C:10](=[O:17])[N:9]([CH2:18][C:19]3[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=3)[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCNCC3)C2=O)c1
Reactant: O=c1[nH]c2ccccc2n1CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(C3CCCCC3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Yield: 72.7 %

Procedure:
tert-Butyl 3-((1-cyclohexyl-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.823 g, 1.92 mmol), 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.58 g, 1.92 mmol), and potassium carbonate (0.39 g, 2.88 mmol) in N,N-dimethylformamide (8 mL) were heated at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as a white solid (0.84 g, 73%); 1H NMR (DMSO-d6); δ 0.93-0.96 (m, 1H); 1.14-1.25 (m, 4H); 1.52 (s, 9H); 1.57-1.62 (m, 9H); 1.79 (m, 2H); 2.29-2.36 (m, 4H); 2.63 (m, 3H); 3.82 (t, J=6.8 Hz, 2H); 4.08 (s, 2H); 4.43 (s, 2H); 6.97-7.01 (m, 3H); 7.14 (d, J=6.4 Hz, 1H); 7.44-7.49 (m, 2H); 7.72 (s, 1H); 7.81 (dt, J=2.4 Hz and 6.4 Hz, 1H); 10.8 (s, 1H); MS for C35H47N5O4 m/z 602 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(O)(=O)C.[N:33]1(C(OC(C)(C)C)=O)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[C:15]1([CH:14]2[C:5]3=[N:4][NH:3][C:2](=[O:1])[C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=43)[NH:12][CH:13]2[C:21]2[CH:22]=[CH:23][C:24]([CH2:25][N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc(CN3CCNCC3)cc1)C2c1ccccc1
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.54 mmol) in dichloromethane (30 mL) was added acetic acid (196 mg, 3.24 mmol) and tert-butyl piperazine-1-carboxylate (304 mg, 1.63 mmol) at room temperature and stirred overnight. Then NaBH(OAc)3 (173 mg, 0.81 mmol) was added to the mixture at 0° C., stirred for one day. The reaction mixture was quenched with aqueous sodium bicarbonate, extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated to give the crude product which was purified by flash chromatography to obtain a solution. To the solution obtained (concentrated to about 50 mL) was added conc. HCl (10 mL) at room temperature and stirred overnight. The mixture was extracted with ethyl acetate for three times, the aqueous phase was concentrated to give 9-phenyl-8-(4-(piperazin-1-ylmethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (127 mg, yield 46%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 3.47 (br s, 7H), 3.60 (m, 1H), 4.32 (s, 2H), 4.38 (d, 1H), 4.83 (d, 1H), 5.41 (br s, 2H), 7.19 (m, 6H), 7.24 (m, 3H), 7.55 (m, 4H), 9.87 (br s, 2H), 12.20 (s, 1H); LC-MS (ESI) m/z: 438 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:9][OH:10])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:2].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].[Na+].[Cl-]>C(Cl)(Cl)Cl>[CH3:11][C:12]([CH3:17])=[CH:13][C:14]([O:10][CH2:9][C:3]1([CH2:1][CH3:2])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)=[O:15]
Reactant: CC(C)=CC(=O)Cl
Reactant: CCC1(CO)COC(=O)N1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1(COC(=O)C=C(C)C)COC(=O)N1

Procedure:
3.1 grams (0.021 mole) 4-ethyl-4-hydroxymethyl-2-oxazolidinone, prepared identically to that discussed in example 1, 2.6 grams (0.022 mole) 3,3-dimethylacryloyl chloride, and 25 milliliters chloroform were mixed in a one-necked round-bottom flask. The procedure employed was identical to that discussed in example 4. 4.10 grams (90% of the yield theoretically expected) of pure product was obtained as a yellow oil. The product exhibited the following spectral data: 1H NMR (CDCl3) δ0.98(t, 3H J=1.2 Hz), 1.65-1.71(m, 2H), 1.92(s, 3H), 2.17(s, 3H), 4.04-4.23(m. 4H), 5.71(s, 1H), 6.43(s, 1H); 13C NMR(CDCl3) δ7.6, 20.6, 27.7, 28.7, 60.3, 66.1, 71.3, 115.2, 159.0, 159.5, 166.2; IR (NaCl) 3215, 3020, 2970, 1785 cm-1 ; MS m/z 227. This monomer can be chlorinated or brominated by the same procedure as in example 1.
Reaction SMILES: Br[C:2]1[O:3][C:4]([Br:23])=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][NH:31][CH3:32].C1COCC1>>[Br:23][C:4]1[O:3][C:2]([N:31]([CH3:32])[CH3:30])=[N:6][C:5]=1[C:7]1[N:11]2[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]2=[N:9][C:8]=1[CH3:22]
Reactant: CNC
Reactant: CCC(CC)c1cc(C)nn2c(-c3nc(Br)oc3Br)c(C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3nc(N(C)C)oc3Br)c(C)nc12
Temperature: 130 °C
Yield: 87 %

Procedure:
67 mg of 3-(2,5-Dibromo-oxazol-4-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.15 mmol), 146 mg of cesium carbonate (0.45 mmol) and 3.0 ml of dimethylamine 2.0M in THF (6 mmol) are placed into a 4 ml of reaction vial and the vial is capped with a Teflon cap. The reaction vial is heated at 130° C. overnight. The reaction mixture is concentrated and applied onto a silica-gel chromatography column (Hexane:AcOE t=3:1) to give 53 mg of the title compound (87%); mass spectrum (m/e): 406; 1H-NMR (CDCl3): 6.72 (s, 1H), 3.37 (m, 1H), 3.15 (s, 6H), 2.58 (s, 3H), 2.53 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J=7.2 Hz).
Reaction SMILES: C([Mg]Br)C.[CH3:5][CH:6]([CH2:9][CH3:10])[C:7]#[CH:8].[CH3:11][C:12]([CH3:22])([C:14](=[O:21])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:13].[Cl-].[NH4+]>C(OCC)C.ClCCl>[CH3:13][C:12]([CH3:22])([C:14]([OH:21])([C:8]#[C:7][CH:6]([CH3:5])[CH2:9][CH3:10])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH3:11]
Reactant: CC(C)(C)C(=O)Cn1cncn1
Reactant: C#CC(C)CC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(C)C#CC(O)(Cn1cncn1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
10 To a solution of ethyl magnesium bromide (20 ml) of a 3M solution in diethyl ether) in dry diethyl ether (30 ml) under N2 at room temperature was added a solution of 3-methyl-1-pentyne (5 g, 0.06 mol) in diethyl ether (20 ml). The resulting mixture was heated under reflux for 1 hour, and then cooled to 0° C. To this mixture was added slowly a solution of 2,2-dimethyl-4-(1,2,4-triazol-1-yl)-butane-3-one (8.4 g, 0.05 mol) in dry dichloromethane (150 ml), and the mixture stirred for 45 minutes, a gelatinous precipitate formed. Ammonium chloride solution was added to the mixture, and the organic layer separated and washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica eluting with diethyl ether (20-100%) in petrol gave 2,2-dimethyl-3-hydroxy-3-(3-methyl-pent-1-yne-1-yl)-4-(1,2,4-triazol-1-yl)-butane) as a white solid (4.29 g) (mpt=59°-60° C.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][CH:24]([C:20]3[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=3)[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCOc1ccc(Br)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-4-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.37 (d, 2H, J=7.6 Hz), 7.26 (m, 3H) 6.97 (d, 1H, J=7.7 Hz), 6.79 (d, 2H, J=7.7 Hz), 4.01 (t, 2H, J=5.6 Hz), 3.08 (d, 2H, J=9.4 Hz), 2.53 (m, 4H), 2.05 (m, 4H), 1.84 (m, 4H), 1.24 (d, 6H, J=5.9 Hz); Anal. Calcd for C24H31BrN2O2.HCl+0.34CHCl3: C, 54.5; H, 6.08; N, 5.22. Found: C, 54.5; H, 6.22; N, 5.22; ESMS m/e: 459.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[F:23][CH2:24][C:25](=O)[CH2:26][F:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CN(C)C=O>ClCCl>[F:23][CH2:24][CH:25]([N:5]1[CH2:6][CH2:7][C:2]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])([F:1])[CH2:3][CH2:4]1)[CH2:26][F:27]
Reactant: O=C(CF)CF
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(OCC2(F)CCN(C(CF)CF)CC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
To a suspension of EXAMPLE 341C (0.100 g) and 1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was added sodium triacetoxyborohydride (0.071 g). After 15 minutes, N,N-dimethylformamide was added dropwise until an orange solution resulted (−15 drops). After stirring overnight additional 1,3-difluoropropan-2-one and sodium triacetoxyborohydride were added. After 3 hours, the reaction was loaded onto silica gel (Reveleris 40 g) and eluted with a gradient of 0.5-5% methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])[CH:10]=[CH:9][C:8]=2[NH2:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[K+].[C:26]([C:28]1[N:29]=[C:30]([C:41]([O-])=[O:42])[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=1)#[N:27].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][CH2:14][S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:16])=[O:17])[CH:10]=[CH:9][C:8]=2[NH:24][C:41]([C:30]2[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:32]=[C:28]([C:26]#[N:27])[N:29]=2)=[O:42])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(CCS(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.7 %

Procedure:
A solution of 132 mg (0.377 mmol) of 2-cyclohex-1-enyl-4-[2-(morpholine-4-sulfonyl)-ethyl]-phenylamine (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with 126 mg (0.414 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 93.9 mg (0.565 mmol) of PyBroP to form a slurry, which was treated with 197 μL (1.13 mmol) of DIEA. The mixture was stirred at RT for 3.5 h, diluted with CH2Cl2 (15 mL), and washed with saturated aqueous NaHCO3 (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 221 mg (98%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H41N5O5SSi, 600.3 (M+H). found 599.8.