Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=NO)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].Cl>O.CO>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=[O:2])[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CC(C)=NO)cc1
Reactant: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphate (131 g) in water (300 ml) was added to 1-(4-carbomethoxyphenyl)propan-2-one oxime (37.5 g) in methanol (200 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (100 ml) added, the mixture extracted with chloroform and the combined chloroform extracts washed with water followed by sodium bicarbonate solution. The chloroform layer was dried (MgSO4) and evaporated to give the title compound as an oil (bp 126°-129°/0.7 mm) which crystallised on standing, (mp 40°-47°). τ (CDCl3) 7.88 (3H, s), 6.28 (2H, s), 6.14 (3H, s), 2.77 (2H, d, J=8 Hz), 2,04 (2H, d, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]2.[C:20](Cl)(Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[O:21]=[C:20]1[N:10]2[C:11]3[C:6]([CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Reaction time: 0.08 h

Procedure:
t-Butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (2.70 g) was dissolved in THF (100 mL) and stirred while a solution of phosgene in THF (20.7 mL of 0.40 M, 0.093 mol) was added. After 5 minutes, triethylamine (2.08 g, 0.020 mol) was added and the solution stirred for an additional 10 minutes. The THF was removed under reduced pressure and the material was partitioned between chloroform (250 mL) and water (20 mL). The chloroform was washed with 4N sodium hydroxide (5 mL) and evaporated. The crude material was combined with that of an earlier reaction (0.002 mol scale) and purified by chromatography on silica gel in 1% methanol:chloroform to give 2.28 g of product. Crystallization from methanol:ether (1:1) gave 1.60 g (54%) white solid, mp 235°-236° C. Anal. Calcd. for C15H19N3O3 : C, 62.26; H, 6.62; N, 14.52. Found: C, 61.65 ; H, 6.94; N, 14.23.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][O:25][NH2:26])[CH2:18][CH2:17]1.C(O)(=O)/C=C/C([O-])=O>>[O:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][O:25][N:26]=[C:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:20][CH2:21]1
Reactant: NOCCCN1CCOCC1
Reactant: O=C1CCCCCCCCCCC1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)O
Product: C1CCCCCC(=NOCCCN2CCOCC2)CCCCC1

Procedure:
Starting from 18.23 g. (0.1 moles) of cyclododecanone and 25.64 g. (0.11 moles) of morpholinopropoxyamine dihydrochloride the title compound is prepared as in Example 13. Yield: 28.4 g. (87%). Hydrogen fumarate, m.p.: 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11]O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[S:13]([O-])(=[O:16])(=[O:15])[CH3:14]>>[CH3:1][O:2][C:3]1(/[CH:9]=[CH:10]/[CH2:11][S:13]([CH3:14])(=[O:16])=[O:15])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(/C=C/CO)CCOCC1
Reactant: CS(=O)(=O)[O-]
Product: COC1(/C=C/CS(C)(=O)=O)CCOCC1

Procedure:
4-methoxy-4-(3-hydroxy-trans-prop-1-enyl)tetrahydropyran, prepared as in step 4, was convened to the corresponding mesylate according to the methodof Crossland and Servis, J. Org. Chem., 35, 3195-3196 (1970).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:44]=1)[CH2:8][C:9]1([CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:14](=[O:15])[O:13]C(C)(C)[O:11][C:10]1=[O:18])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([CH:42]=[C:43]([C:45]([O:47][CH3:48])=[O:46])[CH:44]=1)[CH2:8][C:9]([CH2:19][CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:10]([OH:18])=[O:11])[C:14]([OH:15])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CC2(CCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC(C)(C)OC2=O)cc(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(CC(CCCSC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)C(=O)O)cc(C(C)(C)C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 5-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2,2-dimethyl-5-[3-[(triphenylmethyl)thio]propyl]-[1,3]dioxane-4,6-dione X (11 g, 16.5 mmol) in 1,4-dioxane (15 ml) was added a solution of sodium hydroxide (4.63 g, 115.5 mmol) in H2O (15 mL) at 25° C., and the mixture was stirred at 100° C. for 1 hour. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a 10% aqueous KHSO4 solution. The organic layer was dried over MgSO4, concentrated. The crude material was recrystallized from ethyl acetate/hexane mixture to afford 2-(3-tert-butyl-5-methoxycarbonyl-benzyl)-2-[3-[(triphenyl-methyl)thio]propyl]malonic acid XI (9.0 g, 90%) as a white solid: 1H NMR (CD3OD) δ 1.4 (s, 9H), 1.4 (m, 2H), 1.6 (m, 2H), 2.1 (t, J=8.0 Hz, 2H), 3.2 (s, 2H), 7.1-7.4 (m, 16H), 7.7 (s, 1H), 7.9 (s, 1H); 13C NMR (CD3OD) δ 24.8, 31.8 (3C), 32.4, 33.3, 35.6, 39.0, 59.5, 67.7, 126.2, 127.7, 128.9, 129.6, 130.7, 131.5, 132.9, 137.8, 146.2, 152.6, 170.1, 174.5.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[C:21]([C:18]1[CH:19]=[CH:20][N:15]2[N:14]=[CH:13][C:12]([C:7]3[N:6]=[C:5]4[C:10]([NH:11][C:3](=[O:2])[N:4]4[C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[CH2:24]4)=[CH:9][N:8]=3)=[C:16]2[CH:17]=1)#[N:22]
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.1 %

Procedure:
To a solution of the compound obtained in example 6 (110 mg, 0.22 mmol) in anhydrous DMF (3 mL), N,N-dimethylsulfamoyl chloride (0.03 mL, 0.27 mmol) and anhydrous TEA (0.13 mL, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 39.2 mg of the titled compound (38% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1.[CH2:26]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][C:30]1=[O:39])[C:27]#[CH:28].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[C:27][CH2:26][N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][C:30]3=[O:39])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: COC1N=C(c2ccccc2F)c2cc(I)ccc2-n2c(C)nnc21
Solvent: ClCCl
Solvent: CCO
Product: COC1N=C(c2ccccc2F)c2cc(C#CCN3C(=O)CCc4ccccc43)ccc2-n2c(C)nnc21

Procedure:
The title compound was prepared by coupling rac-6-(2-fluorophenyl)-8-iodo-4-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate/ether to give colorless crystals of rac-1-{3-[6-(2-fluorophenyl)-4-methoxy-1-methyl-4H[1,2,4]triazolo[4,3-a][1,4] benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160°. These crystals contained 0.33 molar equivalents of water.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=1.[CH:26](=O)[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1.C(O)(=O)C.[BH4-].C([Na])#N>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:2]([NH:1][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[C:3]([CH:21]=1)[CH:4]([OH:20])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:6]=1
Reactant: O=Cc1ccco1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCc2ccco2)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 98.3 %

Procedure:
In methanol (15 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) produced in Example (1) and furfural (0.15 g). To the solution were added acetic acid (0.1 g) and cyano sodium borohydride (0.11 g). The mixture was stirred for 40 minutes at 60° C. The reaction mixture was concentrated, to which were added water (30 ml) and ethyl acetate (50 ml), followed by subjecting the mixture to extraction. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 5-chloro-2-(furan-2-ylmethyl)amino-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.6 g) as a colorless oily product.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH:8]=O)[CH2:7][CH2:6]1.[NH2:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([Br:18])=[CH:13][N:12]=1.[BH4-].[Na+]>ClCCl>[Br:18][C:14]1[CH:15]=[C:16]([NH:17][CH2:8][CH:5]2[CH2:7][CH2:6]2)[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: O=CC1CC1
Reactant: Nc1cc(Br)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1ncc(Br)cc1NCC1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid (304 μl) and cyclopropanecarbaldehyde (406 μl) were added to a solution of 2,3-diamino-5-bromopyridine (1000 mg) in dichloromethane (25 ml) at room temperature, followed by stirring for 1 hour. Sodium tetrahydroborate (604 mg) was added to the reaction solution under ice-cooling, and the mixture was stirred with warming to room temperature for 22 hours. The reaction solution was extracted by adding a saturated aqueous sodium bicarbonate solution and dichloromethane. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography to give the title compound (286 mg).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][N:44]=[C:42]([NH:41][C:31]3[CH:32]=[CH:33][C:34]([N:35]4[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]4)=[C:29]([F:28])[CH:30]=3)[N:43]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Cl)cc1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(F)c2)nc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from crude ethyl 3-dimethylamino-2-(4-chloro-benzoyl)-acrylate (89 mg, 0.3 mmol) and N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (80 mg, 0.22 mmol) using in analogous manner the procedure described in example 28b). Obtained as a pale-yellow solid (28 mg, 28%). Mp 232-234° C.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17]COCC.[N+](=C)=[N-].C(O)(=O)C>C(OCC)(=O)C>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:17])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)c1ccc(OCCCC(=O)O)cc1
Agent: C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCCOc1ccc(C(C)=O)cc1

Procedure:
4-(p-Acetylphenoxy)butyric acid (4.1 g.) was suspended in ethyl acetate (80 ml.), and to the suspension was added dropwise an ether solution of diazomethane with stirring under ice-cooling until a color of the diazomethane was appeared. After the stirring was continued at the same temperature for additional half an hour, a small amount of acetic acid was added to the reaction mixture, and then the solution was stirred for a while. This solution was evaporated to dryness under reduced pressure and the residue was treated with a mixture of isopropyl ether and n-hexane (1:1 by volume) to give methyl 4-(p-acetylphenoxy)butyrate (3.83 g.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 66.3 %

Procedure:
6-Methyl-5-nitroisoquinoline (32 g, 170 mmol) was dissolved in DCM (500 mL) and cooled in an ice-acetone bath to 0° C. 3-Chloroperoxybenzoic acid (49.9 g, 289 mmol) (73%) was added in portions while stirring the reaction mixture vigorously. After the addition, the reaction mixture was stirred at 0° C. for 4 h. Upon being warmed to RT, the reaction mixture was partitioned in DCM/NaOH (aq., 1 N). After multiple extractions, the organic layers were combined and washed with brine then dried over Na2SO4. Removal of the solvent in vacuo gave 6-methyl-5-nitroisoquinoline N-oxide as a yellow solid (23 g). MS (M+H)+205.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:54][C:55]1[CH:56]=[C:57](B(O)O)[CH:58]=[CH:59][C:60]=1[F:61]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[C:15]([C:58]4[CH:57]=[CH:56][C:55]([F:54])=[C:60]([F:61])[CH:59]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(F)c(F)c2)=C(c2ccc(F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 81 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-fluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 24 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3,4-difluorophenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=2:3) to obtain the title compound (81%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19](OC)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH:34]([OH:37])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:37][CH:34]([CH3:36])[CH3:35])=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 0.312 g methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate (example 4a) in 5 ml isopropanol is added a solution of a catalytic amount of sodium hydride in 1 ml isopropanol. The mixture is refluxed for 18 h and the solvent is evaporated. The residue is dissolved in methylene chloride and the solution is washed with saturated ammonium chloride solution. The organic phase is dried, filtered, evaporated to give a clear oil which is purified by flash column chromatography using ethyl acetate/hexane (2:3) as the eluent to give as a clear oil isopropyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate.
Reaction SMILES: CO[C:3](=[O:12])[C:4]([C:10]#[N:11])=[C:5]([S:8][CH3:9])SC.[C:13]([CH2:15][C:16]([NH2:18])=[S:17])#[N:14].C([O-])([O-])=O.[K+].[K+].Cl>CS(C)=O>[OH:12][C:3]1[NH:18][C:16](=[S:17])[C:15]([C:13]#[N:14])=[C:5]([S:8][CH3:9])[C:4]=1[C:10]#[N:11]
Reactant: N#CCC(N)=S
Reactant: COC(=O)C(C#N)=C(SC)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSc1c(C#N)c(O)[nH]c(=S)c1C#N
Reaction time: 18 h

Procedure:
2-cyano-3,3-bis-methylsulfanyl-acrylic acid methyl ester Compound 1a (25.0 g, 123 mmol) was combined with 97% 2-cyano-thioacetamide (12.7 g, 123 mmol) and K2CO3 (51.0 g, 369 mmol) in DMSO (300 mL) at room temperature. The reaction was stirred for 18 hrs. The cooled reaction mixture (0° C.) was slowly acidified with 1N HCl. The resultant yellow precipitate was collected by filtration and sequentially washed with 1N HCl, water, MeOH and hexane to give 6-hydroxy-4-methylsulfanyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile Compound 1b (24.7 g, 90% yield). 1H NMR (DMSOd6) δ 2.66 (s, 3H). 13C NMR (DMSOd6) δ 118.1 (CN), 117.3 (CN), 17.4 (SMe). MS 222 (M−).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[SH:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.[OH-].[Na+]>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][S:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: Sc1ccncc1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(SCCCSc2ccncc2)ccnc1CSc1ccncc1
Yield: 69 %

Procedure:
According to the procedure indicated in Example 5, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 4-mercaptopyridine and sodium hydroxide solution yields the title compound; m.p. 116-118° C.; Yield 69% of theory.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:11]([OH:15])[CH2:12][CH2:13][OH:14].O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:14][CH2:13][CH2:12][CH2:11][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: OCCCO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCCOCc1ccccc1
Temperature: 100 °C
Yield: 65 %

Procedure:
Benzyl chloride (104 g, 1.0 m) was added dropwise to a solution of KOH (112 g, 2.0 m) in 100 ml of xylene and 304 g of 1,3-propanediol at 50° C.-60° C. The solution was then heated at 100° C. for 2 hours. Water (400 ml) was added to the cooled solution and the mixture was extracted twice with 600 ml of methylene chloride. The combined methylene chloride extracts were washed three times with 400 ml of water, dried over MgSO4, filtered and evaporated to a yellow oil which was distilled under vacuum. The 98° C.-106° C. (1.5 mm) fraction was collected to give 88.7 g of 3-benzyloxypropanol.
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.CCCCCC>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][Br:27])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)[Si](Oc1ccc(Cl)c(CBr)c1)(c1ccccc1)c1ccccc1

Procedure:
tert-Butyl(4-chloro-3-methylphenoxy)diphenylsilane (88.69 g, 0.233 mol), N-bromosuccinimide (49.8 g, 0.279 mol), and AIBN (3.82 g, 0.023 mol) were heated at reflux in CCl4 (500 mL) for 7 h. The reaction mixture was concentrated in vacuo, dissolved in 10% EtOAc/hexane, the succinimide filtered off, and the filtrate concentrated in vacuo to give a mixture of the mono- and di-bromides. Chromatography (SiO2)(100% hexane) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([NH2:23])=[CH:21][N:22]=2)[N:19]=1.[C:24]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:23][C:20]2[N:18]3[N:19]=[C:14]([N:10]4[CH2:11][CH2:12][CH2:13][C@@H:9]4[C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])[CH:15]=[CH:16][C:17]3=[N:22][CH:21]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: Nc1cnc2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nn12
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: N#Cc1cccc(NC(=O)Nc2cnc3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nn23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a DCM (0.1 mL) solution of (R)-6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-amine (Preparation B; 6 mg, 0.019 mmol) cooled in an ice bath was added 3-cyanophenylisocyanate (14 mg, 0.095 mmol) in DCM (0.1 mL) drop-wise. The reaction was slowly warmed to ambient temperature and stirred for 1 hour. The reaction was diluted with DCM (2 mL), washed with water, and concentrated. The crude material was purified by reverse-phase column chromatography, eluting with 5 to 85% acetonitrile/water to yield the pure final product as a solid (3.2 mg, 37% yield). MS (apci) m/z=460.2 (M+H).
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:12][P+:13]([CH2:18]O)([CH2:16]O)[CH2:14]O.[CH3:20][NH:21][C:22]([NH:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]([CH2:18][P+:13]([CH2:12][N:21]([CH3:20])[C:22]([NH:24][CH3:25])=[O:23])([CH2:14][N:21]([CH3:20])[C:22]([NH:24][CH3:25])=[O:23])[CH2:16][N:21]([CH3:20])[C:22]([NH:24][CH3:25])=[O:23])[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)NC
Reactant: OC[P+](CO)(CO)CO
Agent: O=S(=O)([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CNC(=O)N(C)C[P+](CN(C)C(=O)NC)(CN(C)C(=O)NC)CN(C)C(=O)NC
Yield: 73.9 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium benzenesulfonate (15.61 g, 0.05 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (200 ml), following Example 1, gave 21.91 g (73.9%) of tetrakis(1,3-dimethylureidomethyl)phosphonium benzenesulfonate (I, R=R'=CH3, R"=H, X=SO3C6H5) as a white, crystalline solid, mp 103°-105° C. after three recrystallizations from acetonitrile (3 ml/g). The analytical sample, dried under vacuum for 4 hr at 56° C. (acetone), analyzed as a hydrate.