Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:19]([NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[S:20])#[N:5]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N#Cc1ccccc1N
Product: N#Cc1ccccc1NC(=S)NC(=O)c1ccccc1

Procedure:
Prepared as in Example 1a from 2-aminobenzonitrile and benzoyl isothiocyanate as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.35-7.56 (m, 3H), 7.67 (t, 1H), 7.75-7.76 (d, J=5.2 Hz, 2H), 7.89-7.91 (d, J=7.2 Hz, 2H), 7.98-8.01 (dd, J1=1.6 Hz, J2=8.2 Hz, 2H), 11.90 (s, 1H), 12.54 (s, 1H). MS 282 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]=2[CH3:28])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH2:39][CH2:40]Br)(=[O:37])[CH3:36].CN(C)C=O>O>[C:35]([O:38][CH2:39][CH2:40][N:20]1[C:21]2[C:26](=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:18]([C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:17])=[C:19]1[CH3:28])(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCn1c(C)c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)c2cc(F)ccc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
N-(3-Cyano-4-neopentyloxyphenyl)-5-fluoro-2-methyl-1H-indole-3-carboxamide ¼ hydrate (0.8 g) obtained in Example 9,. potassium carbonate (0.2 g) and 2-bromoethyl acetate (0.4 g) were added to dimethylformamide (5 ml) and the mixture was stirred at 40° C. for 3 hr. Then the reaction mixture was treated with water and the oganic layer was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was separated and purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.3 g). melting point: 124-125° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=1[CH:11]=[CH:12][C:13]([OH:15])=O.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:33]([N:35]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH2:38][C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[NH2:40])=[CH:36]1)[CH3:34]>C(Cl)Cl>[CH2:33]([N:35]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:37]([CH2:38][C@@H:39]([C:41]([O:43][CH3:44])=[O:42])[NH:40][C:13](=[O:15])[CH:12]=[CH:11][C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[F:8])=[CH:36]1)[CH3:34]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCn1cc(C[C@H](N)C(=O)OC)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.1 %

Procedure:
Triethylamine (1.5 mL), 2-fluorocinnamic acid (1.8 g) and WSC.HCl (2.1 g) were at 0° C. added to methylene chloride (70 mL) suspension of the compound obtained in Example 143 (2.8 g). The mixture was stirred for 4 hours at room temperature. The reaction mixture was washed with water, and thereafter the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (chloroform), to give the captioned compound (2.7 g, 70%) as crystals.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[CH3:8][N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][NH:12]2.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(Cl)Cl>[CH3:8][N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Cc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1nsc(N2C[C@@H]3C[C@H]2CN3C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A solution of 1.04 g of 5-chloro-3-methyl-1,2,4-thiadiazole, prepared by the procedure of J. Goerdeler, Chim. Ber., 1957, 90, 182, in 2 ml of tetrahydrofuran is added over one hour to a solution of 0.825 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.77 g of potassium carbonate in 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, diluted with methylene chloride and the organic layer is washed with water. The methylene chloride solution is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride) to give 0.56 g of the desired product:
Reaction SMILES: [OH-:1].[Ca+2].[OH-].[CH:4]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[C:7]([CH3:8])[C:5]=1O>>[C:7]1([CH3:8])[CH2:9][CH2:10][CH:11]([C:12]([CH2:14][OH:1])=[CH2:13])[CH2:4][CH:5]=1
Reactant: Cc1ccc(C(C)C)cc1O
Reactant: [OH-]
Agent: [Ca+2]
Product: C=C(CO)C1CC=C(C)CC1
Temperature: 222.5 °C

Procedure:
A mixture of 300 parts of 8,9-limonene oxide, 6 parts of calcium hydroxide and 6 parts of carvacrol was refluxed at 215-230° C. for 2 hours in a three-necked flask equipped agitator, Dean-Stark trap, and temperature probe. After cooling and filtration 290 parts of the mixture containing 30% of unreacted epoxide and 43% 1,8-p-menthadien-10-ol (61% selectivity) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH2:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH3:29]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([NH:33][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2ccccc2c1=O
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)Nc1ncc(OCC2CC2)c(-c2cn(C)c(=O)c3ccccc23)n1

Procedure:
The title compound of Example 152, step 5 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 9.00 (s, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.69 (m, 2H), 7.57 (t, J=7.6 Hz, 1H), 3.86 (d, J=6.8 Hz, 2H), 3.70 (s, 3H), 3.63 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.13 (m, 1H), 0.57 (m, 2H), 0.25 (m, 2H). LCMS: 415.0 (M+1)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:9](=[O:11])N)=[C:6]([NH2:8])[N:7]=1.C.[OH-:13].[Na+]>O>[NH2:8][C:6]1[C:5]([C:9]([OH:11])=[O:13])=[N:4][CH:3]=[C:2]([NH2:1])[N:7]=1
Reactant: [OH-]
Reactant: NC(=O)c1ncc(N)nc1N
Agent: C
Agent: [Na+]
Solvent: O
Product: Nc1cnc(C(=O)O)c(N)n1

Procedure:
A slurry consisting of 1.60 g of 3,5-diamino-6-carbamoylpyrazine, from Example 4, in 20 ml of 10% aqueous sodium hydroxide was heated at reflux for 2 hours, diluted to 100 ml with hot water and the resulting homogeneous solution was decolorized with Darco. Careful acidification to pH 1 gave a precipitate which was collected from the chilled solution by filtration. The collected material was washed twice, each time with small portions of water and methanol and dried yielding 0.92 g of 3,5-diaminopyrazinoic acid as a light powder, mp 169° (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[CH:11](Br)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: CC(C)Br
Product: CC(C)Oc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and isopropylbromide according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 1.36 (6H, d, J=6.4 Hz), 2.40 (1H, s), 4.55-4.59 (1H, m), 4.61 (2H, s), 6.86 (1H, d, J=2.0 Hz), 6.89 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.18 (1H, d, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([CH2:15][NH:16]C4CCNCC4)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37]N[CH2:35][CH2:34]2)=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:24]([N:8]1[C:9]2[C:14]([CH2:15][N:16]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)=[CH:13][N:12]=[CH:11][C:10]=2[N:23]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:25]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCNCC3)c21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCn1c(-c2nonc2N)nc2cncc(CN3CCN(c4ccc(F)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product of Example 191 Step 1 (0.10 g, 0.38 mmole) in 1,2-dichloroethane (5 ml) was treated with 1-(4-fluorophenyl)piperazine (0.10 g, 0.58 mmole) and stirred at ambient temperature for 15 minutes. Sodium triacetoxyborohydride (0.16 g, 0.76 mmole) was added and the reaction mixture stirred at ambient temperature for 18 hours. The mixture was diluted with dichloromethane, washed (×2) with saturated sodium hydrogen carbonate solution followed by saturated brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to afford the title compound; MS (ES+) m/e 357 [M+H]+. The following examples were prepared from the product of Example 191 Step 1 using the method described in Example 200.
Reaction SMILES: [C:1]([C:3](=[C:7]([S:10][CH3:11])SC)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:12][N:13]([CH3:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)C>[C:1]([C:3](=[C:7]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]([CH3:21])[CH3:12])=[CH:15][CH:16]=1)[S:10][CH3:11])[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CSC(SC)=C(C#N)C(N)=O
Reactant: CN(C)c1ccc(N)cc1
Solvent: CCO
Product: CSC(Nc1ccc(N(C)C)cc1)=C(C#N)C(N)=O
Temperature: 75 °C
Yield: 91 %

Procedure:
To a solution of 1.00 g (2-cyano-3,3-bis(methylthio)acrylamide) in 25 mL of ethanol was added 0.720 g (1.1 eq.) of N,N-dimethyl-p-phenylenediamine and the reaction was stirred at 75° C. until starting amide was absent as confirmed by HPLC. Once complete (18 hrs), the reaction was brought to room temperature and filtered to obtain 2-cyano-3-((4-(dimethylamino)phenyl)amino)-3-(methylthio)acrylamide as an off white to light yellow powder. The product was allowed to dry under vacuum for 1 hr (1.133 g, 91% yield).
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>O1CCCC1>[C:1]([O:4][CH:5]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(CCCCCCCCO)c1coc([Si](C)(C)C)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)OCCCCCCCCC(OC(C)=O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(1-acetoxy-9-hydroxynonyl)-2-trimethylsilylfuran (0.075 g, 0.221 mmol) and pyridine (0.056 g, 0.662 mmol) in tetrahydrofuran (2 ml) under argon at 0° was added dropwise acetyl chloride (0.052 g, 0.662 mmol). The mixture was warmed to room temperature, stirred for one hour, quenched with water and extracted into ethyl ether. The organic portion was washed with 10% hydrochloric acid, saturated sodium bicarbonate, aqueous 5% cupric sulfate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil. Purification by flash chromatography (silica, 5 to 10% ethyl acetate/hexane) gave the desired product.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH3:17])=[O:15])[N:2]=1.OC[CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16][CH2:17][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:15])[N:2]=1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: OCCN1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: O=C(OCCN1CCOCC1)c1cc2c(cn1)[nH]c1ccccc12
Temperature: 25 °C
Yield: 63 %

Procedure:
A suspension of β-carboline-3-carboxylic acid, methyl ester (5.3 g, 23.4 mmol), 4-(2-hydroxyethyl) morpholine (4.62 g, 35 mmol), 4-dimethylaminopyridine (1.2 g, 9.8 mmol), 4 Å molecular sieves (5 g) and xylene (250 mL) was heated at reflux for 48 hours. The reaction mixture was cooled to room temperature, concentrated under vacuum, and the resulting slurry was partitioned with CH2Cl2 (250 mL). The mixture was filtered under vacuum and the residue was washed with CH2Cl2 (2×25 mL). Combined organic layers were washed several times with water, dried over Na2SO4, and concentrated. Purification of crude product by column chromatography on silica with 8% 2M NH3—CH3OH in CH2Cl2 as eluent furnished the desired product (4.8 g, 64%) as a pale yellow solid. 1H NMR (CDCl3) δ9.09 (s, 1H), 8.88 (s, 1H), 8.21 (d,J=7.9 Hz, 1H), 7.63 (d,J=8.1 Hz, 1H), 7.63 (d,J=8.1 Hz, 1H), 7.62 (t,J=7.38 (t, J=7.4 Hz, 2H), 4.63 (t, J=6.1 Hz, 2H), 3.73 (t, J=4.6 Hz, 4H), 6.1 Hz, 2H), 2.59 (t, J=4.6 Hz, 4H); MS (APCI; (M+H)+) m/z 326.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: CCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 75.6 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and n-butylamine (0.0134 g, 0.184 mmol) gives the title compound (0.0458 g, 75.7%): TOF MS ES+ 330.2 (M+H)+, HRMS calcd for C18H24N3O3 330.1818 (M+H)+, found 330.1802, time 0.39 min, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.9 min, 100% purity.
Reaction SMILES: O=[C:2]([CH2:21][CH3:22])[CH2:3][CH:4]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8].CC1C(C2(C3C(C)=C(Br)C(O)=C(C(C)C)C=3)OS(=O)(=O)C3C2=CC=CC=3)=CC(C(C)C)=C(O)C=1Br.[CH2:58]([NH2:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:58]([NH:65][CH:2]([CH2:21][CH3:22])[CH2:3][CH:4]([P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1
Reactant: NCc1ccccc1
Reactant: CCOP(=O)(OCC)C(CC(=O)CC)P(=O)(OCC)OCC
Agent: Cc1c(C2(c3cc(C(C)C)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(C(C)C)c(O)c1Br
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(CC(CC)NCc1ccccc1)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
To a stirred solution of tetraethyl 3-oxopentane-1,1-bisphosphonate (0.50 g, 1.4 mmol) in methanol (5 ml) was added a small amount of bromothymol blue and benzylamine (0.75 g, 7.0 mmol). Acetic acid was added dropwise until the solution turned yellow (pH=6), and NaCNBH3 (57 mg, 0.9 mmol) was added. The resulting yellow solution was stirred at room temperature for 2 days, at which time more NaCNBH3 (20 mg) was added. After stirring a total of 4 days, the reaction was quenched by adding concentrated HCl until the pH was less than 1, and the solvents were removed in vacuo. The residue was taken up in water (10 ml) and washed with diethyl ether (2×20 ml). The aqueous layer was made basic (pH greater than 10) by the addition of solid KOH, saturated with NaCl, and extracted with dichloromethane (5×25 ml). The combined extracts were dried (Na2SO4) and concentrated to give tetraethyl 3-benzylaminopentane-1,1-bisphosphonate. This material was hydrolyzed by heating at reflux in concentrated HCl (6 ml) for 20 hours. The volatiles were removed under vacuum, the residue dissolved in water (10 ml) and concentrated under vacuum to give 0.49 g of Compound No. 159 as a hygroscopic foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](I)[CH3:22]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:6]([O:8][CH2:21][CH3:22])=[O:7])#[N:2]
Reactant: CCI
Reactant: COCc1cc(C#N)cc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C#N)cc(COC)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a solution of 3-cyano-5-methoxymethyl-benzoic acid (90 mg, 0.469 mmol) in acetonitrile (3 mL) was added cesium carbonate (199 mg, 0.1 mmol) and ethyl iodide (44 μL, 0.563 mmol), respectively. The reaction mixture was stirred at reflux for 4 h. Upon cooling to room temperature, the reaction mixture was filtered and the filtrated was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo to afford ethyl 3-cyano-5-methoxymethyl-benzoate (88 mg, 70%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:23][C:24]4[S:25][C:26]([Cl:29])=[CH:27][CH:28]=4)(=[O:21])=[O:20])[CH2:15][C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:42]>C(OCC)(=O)C>[NH2:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:23][C:24]4[S:25][C:26]([Cl:29])=[CH:27][CH:28]=4)(=[O:20])=[O:21])[CH2:15][C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C1CN(S(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1ccc2c(Cl)cnnc2c1
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1cnnc2cc(CN3CCN(S(=O)(=O)C=Cc4ccc(Cl)s4)CC3=O)ccc12
Temperature: 120 °C
Yield: 35.8 %

Procedure:
1-(4-Chlorocinnolin-7-ylmethyl)-4-[2-(5-chlorothiophen-2-yl)-ethenesulfonyl]-piperazin-2-one (0.06 g, 0.12 mmol) is treated with phenol (0.20 g) and ammonium acetate (0.2 g, 2.6 mmol) and heated to 120° C. for 45 minutes. The reaction mixture is cooled, diluted with ethyl acetate and washed with 1 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (20% aqueous TFA (0.1%)/acetonitrile to 100% acetonitrile). Fractions containing the desired product are lyophilized to obtain the title compound (0.02 g, 0.043 mmol). MS m/z: [M+H]+=464; 1H NMR (CD3OD, 300 MHz) δ8.6 (s, 1H), 8.4 (d, 1H), 7.75 (d, 1H), 7.65 (d, 1H), 7.35 (d, 1H), 7.1 (d, 1H), 6.8 (d, 1H), 4.9 (s, 2H), 4.05 (s, 2H), 3.6 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([N:17]([CH3:22])[C:18](=[O:21])[CH:19]=[CH2:20])=[CH:12][N:11]=1.C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:9][C:10]1[N:11]=[C:12]2[C:13]([N:17]([CH3:22])[C:18](=[O:21])[CH2:19][CH2:20][N:1]2[CH:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[CH:14][N:15]=1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Reactant: CN1CCC(N)CC1
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCC(N2CCC(=O)N(C)c3cnc(Cl)nc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
4-Amino-1-methylpiperidine (Fluorochem; 200 mg, 1.74 mmol), N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 337 mg, 1.45 mmol) Triethylamine (404 μL, 2.9 mmol), Titanium Tetra-ethoxide (152 μL, 0.725 mmol) and DCM (5 mL) were combined and stirred at room temp for 1 hr, heated at 40° C. for 3 hrs then cooled to room temperature. The reaction mixture was washed with water then gravity filtered through a PTFE cup, the aqueous layer containing the titanium emulsion was washed with further DCM (3×10 mL) and the combined organic solutions gravity filtered through a PTFE cup and solvents evaporated. The residue was dissolved in DCM and purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 0-5% 2M ammonia in MeOH/DCM. Product containing fractions were combined and evaporated to give the title compound as a yellow solid (39 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:18][CH3:19])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:20][N:21]([CH:23](OC)OC)[CH3:22]>C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:6]=[C:7]([O:18][CH3:19])[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][C:2]=1[N:1]=[CH:20][N:21]([CH3:23])[CH3:22])#[N:5]
Reactant: COC(OC)N(C)C
Reactant: COc1cc(C#N)c(N)cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C#N)c(N=CN(C)C)cc1OCc1ccccc1

Procedure:
2-amino-4-benzyloxy-5-methoxy benzonitrile (102 g, 400 mmol) in toluene (1.51) was reacted with DMF-DMA (110 ml, 780 mmol) at reflux for 5 hours. The solvent was evaporated, the residue triturated with ether to give title compound as yellow solid.
Reaction SMILES: [CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].O1C=C[CH:37]=[C:36]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH:36]=[CH2:37])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3cc(F)ccc3C(CCCC)(CCCC)C1=O)N2
Temperature: 50 °C
Yield: 523.6 %

Procedure:
A solution of the compound of Example 20B (120 mg, 0.20 mmol), tri-(2-furyl)phosphine (5 mg, 0.020 mmol), tris-(dibenzylideneacetone)palladium (0) (9 mg, 0.010 mmol) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 10 min, during which time the solution changed from a deep maroon color to pale green. The solution was treated with vinyltributylstannane (118 □L, 0.403 mmol) followed by warming at 50° C. for 1.5 h. The solution was cooled, diluted with ethyl acetate and stirred for 1 h with 1 M KF solution. The mixture was filtered through celite® and the layers separated. The organic layer was washed with saturated NaCl solution and dried over Na2SO4. Concentration in vacuo afforded an oil which was purified by flash chromatography eluting with ethyl acetate in hexane. These procedures afforded the title compound (52 mg, 52%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 0.59 (m, 2 H) 0.73 (m, 6 H) 0.89 (m, 2 H) 1.15 (m, 4 H) 1.88 (m, 2 H) 2.31 (m, 2 H) 5.41 (d, J=11.03 Hz, 1 H) 5.85 (d, J=17.65 Hz, 1 H) 6.74 (dd, J=17.47, 10.85 Hz, 1 H) 7.30 (m, 2 H) 7.43 (m, 2 H) 7.68 (m, 1 H) 7.94 (m, 2 H) 16.80 (s, 1 H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1O)([CH3:4])([CH3:3])[CH3:2].C1(S(O)(=O)=O)C=CC=C(S(O)(=O)=[O:19])C=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:19])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=S(=O)(O)c1cccc(S(=O)(=O)O)c1
Product: CC(C)(C)c1ccc(O)cc1
Temperature: 150 °C
Yield: 84 %

Procedure:
Two grams of ortho-tertiary-butyl phenol was mixed with 1% of meta-benzenedisulfonic acid and heated in a test tube for 1.5 hours with occasional stirring at 150°C. Analysis gave 84.0% para-tertiary-butyl phenol; the remaining components consisted of its isomers.