Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[CH:19]=[CH:18][CH:17]=[N:16][C:8]=2[NH:9][C:10]2[CH:15]=[N:14][CH:13]=[CH:12][C:11]/1=2)C.[Cl-].[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28]([NH2:30])=[NH2+:29].[O-]CC.[Na+].C(OCC)(=O)C>C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[CH2:26][NH:27][C:28]1[N:30]=[CH:4][C:5]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]=3[NH:9][C:8]3[N:16]=[CH:17][CH:18]=[CH:19][C:7]=3[C:6]=2[N:29]=1
Reactant: NC(=[NH2+])NCc1cccc(Cl)c1
Reactant: CN(C)/C=C1/C(=O)c2cccnc2Nc2cnccc21
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1cccc(CNc2ncc3c(n2)-c2cccnc2Nc2cnccc2-3)c1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A mixture of (E)-6-((dimethylamino)methylene)-6,11-dihydro-5H-dipyrido[2,3-b :4′,3′-f]azepin-5-one (0.303 g), 1-(3-chlorobenzyl)guanidinium chloride (0.500 g) and sodium ethoxide (21% solution in ethanol) (0.5 mL) in absolute ethanol (15 mL) was refluxed in for 3 hours. The reaction mixture was cooled to room temperature and poured into ethyl acetate (150 mL), washed with water (200 mL), dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to yield a brown solid. The crude product was purified by flash chromatography (SiO2, gradient 100% ethyl acetate to 5% methanol in dichloromethane) to give the pure desired product, N-(3-chlorobenzyl)-9H-dipyrido[2,3-b:4′,3′-f]pyrimido[4,5-d]azepin-2-amine as a bright yellow solid (0.134 g). M.p.=195-196° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.46-8.07 (m, 7H), 7.42-7.28 (m, 4H), 7.09 (brs, 1H), 4.58 (s, 2H); LCMS (M+H)=387.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)=[O:10])=[CH:5][CH:4]=1.[C:20]([CH2:22][C:23]([NH2:25])=[S:24])#[N:21]>N1CCCCC1.C(O)C>[CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:10])[NH:25][C:23](=[S:24])[C:22]([C:20]#[N:21])=[C:11]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C(=O)C(=O)c2ccccc2)cc1
Reactant: N#CCC(N)=S
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C2(O)NC(=S)C(C#N)=C2c2ccccc2)cc1

Procedure:
A mixture of 10.1 g. p-dimethylaminobenzil, 3.2 g. cyanothioacetamide, 10 drops of piperidine and 100 ml. ethanol is stirred for 12 hours at ambient temperature. The precipitated product is filtered off with suction, washed with chloroform and recrystallised from ethanol. There are obtained 6.0 g. of the desired product in the form of yellow crystals; m.p. 184°-185° C. (decomp.).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Cl.[CH3:13][C:14]1([CH3:21])[NH:18][C:17](=[S:19])[NH:16][C:15]1=[S:20].C[O-].[Na+]>CO>[CH3:2][N:3]([CH3:12])[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][S:19][C:17]1[N:16]=[C:15]([S:20][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N:3]([CH3:12])[CH3:2])[CH:5]=2)[C:14]([CH3:21])([CH3:13])[N:18]=1
Reactant: CN(C)c1cccc(CCl)c1
Reactant: CC1(C)NC(=S)NC1=S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN(C)c1cccc(CSC2=NC(C)(C)C(SCc3cccc(N(C)C)c3)=N2)c1

Procedure:
Initially, 3.1 g of 3-dimethylaminobenzylchloride hydrochloride was added to a mixture of 0.8 g of 5,5-dimethyl-2,4-dithiohydantoin and 1.34 g of sodium methoxide in 50 mL of methanol (MeOH). The reaction mixture was treated following the procedure used in Example 56, and purified by column chromatograph (CHCl3) to give the desired compound in the form of a syrup. The yield of this compound was 1.65 g with a yield ratio of 82.9%.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)=[CH:17][CH:18]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CN1CCNCC1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCN(C)CC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 76 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with 1-methylpiperazine (1 mL) in MeOH (8 mL) under reflux to give the desired product (60 mg, 76%, Z/E=1/1.7) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.12 & 7.08 (d, J=8.8 Hz, 2H), 7.00 (d, J=8.8 Hz, 1H), 6.83 & 6.78 (d, J=8.8 Hz, 2H), 6.72 & 6.69 (d, J=8.8 Hz, 2H), 6.45 & 6.44 (s, 1H), 6.42 (d, J=8.8 Hz, 2H), 4.12 & 3.93 (t, J=5.6 Hz, 2H), 2.84 & 2.73 (t, J=5.6 Hz, 2H), 2.40-2.62 (m, 10H), 2.31 & 2.82 (s, 3H), 0.91 (t, J=7.2 Hz, 3H); m/z=517[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:23])[CH2:21][CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[C:14]([C:20](=[O:23])[C:21]=1[CH3:22])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[O:24]
Reactant: CCC(=O)c1ccc(Cl)cc1N(C(=O)C(=O)OC)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(C)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
A stirred suspension of N-(5-chloro-2-propionyl-phenyl)-N-phenyl-oxalamic acid methyl ester (15.0 g, 43.5 mmol) in methanol (200 mL) was treated with potassium carbonate (35.0 g, 253 mmol) at 25° C. The mixture was then heated at 80° C. for 1 hr. At this time, the reaction was cooled to 25° C. The resulting solids were collected by filtration through a sintered glass funnel and then washed with methanol (2×50 mL). The filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (500 mL) and was washed with water (2×200 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solids were triturated with hexanes and diethyl ether to afford 7-chloro-3-methyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (10.5 g, 73.4%). 1H NMR (DMSO-d6) δ ppm 8.24 (d, J=8.7 Hz, 1H) 7.28-7.78 (m, 6H) 6.69 (d, J=1.7 Hz, 1H) 3.49 (s, 3H) 1.97 (s, 3H). MS calcd. for C18H14ClNO3 [(M+H)+] 328.0 found 327.9.
Reaction SMILES: [CH2:1]([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[B:12]([O:21]C(C)C)(OC(C)C)[O:13]C(C)C.Cl>C1COCC1>[CH:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:1][B:12]([OH:21])[OH:13]
Reactant: [Li]CCCC
Reactant: Brc1ccsc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)Cc1ccsc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 73.2 %

Procedure:
n-Butyllithium (2.5 M solution in hexane, 20 ml, 50 mmol) was added dropwise to a solution of 3-bromothiophene (8.15 g, 50 mmol) in THF (20 ml) at -78° C. under an argon atmosphere. The resulting solution was stirred at -78° C. for 45 min, and then added to a solution of triisopropyl borate (9.4 g, 50 mmol) in THF at -78° C. over 30 min through a steel cannula. The resulting reaction mixture was stirred at room temperature for 12 h and was decomposed by the addition of 100 ml 1N HCl. The aqueous layer was extracted with ether (2×100 ml) and the combined organic layers was extracted with 1 M NaOH (3×30 ml), the aqueous extract was acidified with concentrated HCl to pH 2 and extracted with ether (3×50 ml). The combined ether extract was washed once with water, dried over MgSO4 and filtered. Removal of the solvent gave 3-thenylboronic acid as a solid (5.2 g, 80% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([CH2:25]O)[CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([CH2:25][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:24][CH2:23]1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCC1CC1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCC1CC1
Yield: 83 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclopropanemethanol (28 μL, 0.34 mmol) as the coupling partner. Chromatography (1: 1 methanol:dichloromethane) through SiO2 yielded 49 mg (83%) of the titled compound as a white solid. ESI-MS m/z 346 (MH+), 344 (M−H−).
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:18][N:17]=2)=[CH:12][CH:11]=1>>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([S:21]([NH2:24])(=[O:23])=[O:22])[S:18][N:17]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2nsc(S(N)(=O)=O)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nc(-c2ccc(O)cc2)ns1
Temperature: 0 °C
Yield: 7.5 %

Procedure:
To 35 g of pyridine hydrochloride at 200° was added 28 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide with stirring. The resulting mixture was maintained at 200°-4° for 10 minutes, cooled slightly, poured into excess ice water and extracted with ethyl acetate (3x). The organics were dried over anhydrous magnesium sulfate and concentrated to give 2.0 g of solid. Flash chromatography using 10% ethyl acetate/dichloromethane as eluent gave 1.0 g of solid. This was combined with 0.5 g of the same compound from a previous reaction and recrystallized from water using decolorizing carbon to give 0.95 g of solid, m.p. 219°-221°.
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:46])[C:12]([N:14]1[CH2:34][CH:33]([O:35][C:36]2[CH:41]=[CH:40][C:39]([CH:42]=COC)=[CH:38][CH:37]=2)[CH2:32][C@H:15]1[C:16]([O:18]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:47][C:48]1[CH:53]=[C:52]([Cl:54])[C:51]([S:55]([NH2:58])(=[O:57])=[O:56])=[CH:50][C:49]=1[S:59]([NH:62][CH3:63])(=[O:61])=[O:60].[C:64]1(OC)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[NH2:58][S:55]([C:51]1[C:52]([Cl:54])=[CH:53][C:48]2[NH:47][CH:63]([CH2:42][C:39]3[CH:38]=[CH:37][C:36]([O:35][CH:33]4[CH2:34][N:14]([C:12](=[O:13])[C@H:11]([CH3:46])[CH2:10][S:9][C:1](=[O:8])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[C@H:15]([C:16]([OH:18])=[O:17])[CH2:32]4)=[CH:41][CH:40]=3)[N:62]([CH3:64])[S:59](=[O:61])(=[O:60])[C:49]=2[CH:50]=1)(=[O:56])=[O:57]
Reactant: COc1ccccc1
Reactant: COC=Cc1ccc(OC2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)[C@H](C)CSC(=O)c3ccccc3)C2)cc1
Reactant: CNS(=O)(=O)c1cc(S(N)(=O)=O)c(Cl)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CC(Oc2ccc(CC3Nc4cc(Cl)c(S(N)(=O)=O)cc4S(=O)(=O)N3C)cc2)C[C@H]1C(=O)O

Procedure:
A mixture of (S)-1-[(S)-3-(benzoylthio)-2-methyl-1-oxopropyl]-4-[4-(2-methoxyethenyl)phenoxy]-L-proline, diphenylmethyl ester (4.0 g., 6.3 mmole), 4-amino-6-chloro-N3 -methyl-1,3-benzenedisulfonamide (1.89 g., 1 eq.), 4 ml. anisole, and 130 mg. p-toluenesulfonic acid in 200 ml. of acetonitrile is refluxed. 80 ml. of acetonitrile is distilled off in order to azeotrope off water. The reaction appears to be complete as soon as the distillation is finished. The reaction solution is evaporated and the residue is triturated with diethyl ether. The solid is flash chromatographed on LPS-1 silica eluting with ethyl acetate:acetone (1:1) followed by 10% acetic acid:acetone. After concentrating to a residue, water is added and the gummy solid is absorbed on a filter pad and washed with water to remove acetic acid. The product is then washed from the pad with ethyl acetate. The ethyl acetate solution is washed with water, dried (Na2SO4), and concentrated to a residue (3 g.). A portion of this residue is run through an LH-20 (methanol) column to give an analytically pure sample of (S)-4-[4-[[7-(aminosulfonyl)-6-chloro-3,4-dihydro-2-methyl-1,1-dioxo-2H-1,2,4-benzothiadiazin-3-yl]methyl]phenoxy]-1-[(S)-3-(benzoylthio)-2-methyl-1-oxopropyl]-L-proline; m.p. 228° (decomposition); [α]D =-31.7° (c=1.0%, methanol). TLC (silica, methylene chloride:methanol:acetic acid, 8:1:1) Rf =0.52.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:28][S:29]([O:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1O
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1OS(C)(=O)=O
Temperature: 4 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To an ice-cooled and stirred solution of ethyl 2-({2-hydroxy-4-[4-(methylsulfonyl)phenoxy]phenyl}hydrazono)propanoate (5.8 g) in pyridine (60 mL) was added methanesulfonyl chloride (1.4 mL), and the mixture was stirred at 4° C. for 1 h and then at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with aqueous citric acid solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by short silica gel chromatography (ethyl acetate) to give light orange crystals, which were washed with ethyl acetate-hexane to give the title compound (6.49 g, 93%) as light orange crystals. MS 471 (MH+).
Reaction SMILES: [NH2-:1].[Na+].N.[C:4]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[H][H]>O>[C:4]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:12]2[CH:13]=[C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])[CH:9]=[CH:10][N:1]=2)[CH:9]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccncc1
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1ccnc(-c2cc(C(C)(C)C)ccn2)c1
Temperature: 135 °C
Yield: 24.7 %

Procedure:
In a one-liter, three-neck flask, equipped with a stirrer and dropping funnel, was prepared one mole of sodamide (23.0 g of sodium and iron catalyst) in 700 cc of liquid ammonia. The ammonia was replaced with 589.7 g (4.37 moles) of 4-t-butylpyridine. The mixture was heated to 135° C. at which time the purple reaction mixture began evolving hydrogen. The reaction was continued for 3.1 hours at 135°-149° C. until hydrogen evolution became slow. The reaction mixture was cooled to 100° C. and hydrolyzed with 100 cc of water. The oil layer was separated at 40° C. The aqueous layer was extracted with 50 cc of xylene. The oil layer and xylene extract were charged to a Vigreaux column for distillation. Xylene and about 300 g of unreacted 4-t-butylpyridine were distilled under vacuum. The residue was cooled to room temperature, allowing 4,4'-di-(t-butyl)-2,2'-bipyridyl to crystallize. It was filtered and washed with acetone to give 66.4 g of 4,4'-di-(t-butyl)-2,2'-bipyridyl with a melting point of 159°-160° C.
Reaction SMILES: OC(C(F)(F)F)=O.C([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][C:22]2[CH:23]=[C:24]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][CH:33]=3)[C:25]3[N:26]([CH:28]=[CH:29][N:30]=3)[N:27]=2)[CH2:16]1)C1C=CC=CC=1.C(N1CCCC(N)C1)C1C=CC=CC=1>C(O)(=O)C.[Pd].CO>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:32]([NH:31][C:24]2[C:25]3[N:26]([CH:28]=[CH:29][N:30]=3)[N:27]=[C:22]([NH:21][CH:17]3[CH2:18][CH2:19][CH2:20][NH:15][CH2:16]3)[CH:23]=2)=[CH:37][CH:36]=1)[CH3:40]
Reactant: CCOc1ccc(Nc2cc(NC3CCCN(Cc4ccccc4)C3)nn3ccnc23)cc1
Agent: [Pd]
Agent: NC1CCCN(Cc2ccccc2)C1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOc1ccc(Nc2cc(NC3CCCNC3)nn3ccnc23)cc1
Yield: 6.8 %

Procedure:
To a mixture of a N-(1-benzylpiperidin-3-yl)-N8-(4-ethoxyphenyl)imidazo[1,2-b]pyridazine-6,8-diamine TFA salt (14 mg, 0.021 mmol), prepared by the method of example I(1) using 1-benzylpiperidin-3-amine in place of trans-1,4-diaminocyclohexane in step (1d), and MeOH (5 mL) in a 500 ml PARR bottle was added 10% Pd/C (20 mg) and 3 drops of glacial acetic acid. The PARR bottle was then charged with H2 at 55 psi and allow to shake at room temperature for hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC followed by neutralization with ion exchange resin to furnish 0.5 mg (7%) of the title compound 1H NMR (500 MHz, MeOH) δ ppm 7.57 (1H, s), 7.31 (1H, s), 7.24 (2H, d, J=8.7 Hz), 6.97 (2H, d, J=8.7 Hz), 5.89 (1H, s), 4.05 (2H, q, J=6.9 Hz), 3.85 (1H, m), 3.45 (1H, m), 3.10 (1H, m), 2.85 (1H, m), 2.75 (1H, m), 2.05 (1H, m), 1.90 (1H, m), 1.70 (1H, m), 1.55 (1H, m), 1.39 (3H, t, J=6.9 Hz), LC/MS, m/e 353 (M+1). HPLC Rt, 2.04 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([Mg]Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1.CN1C(=O)CCC1>[CH2:25]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCC[Mg]Cl
Reactant: COC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.05 h
Yield: 92 %

Procedure:
To a solution of methyl 4-chlorobenzoate (300 mg, 1.76 mmol) and Fe(acac)3 (71 mg, 0.2 mmol) in THF (7 mL) and NMP (1.1 mL) at −60° C. is added a solution of C14H29MgCl (1M in THF, 2.3 mL). The mixture immediately turns black and becomes viscous after 3 min. Work-up as described above provides methyl 4-(tetradecyl)benzoate as a low-melting solid (92%). Mp=28–29° C. 1H NMR (300 MHz, CDCl3): δ 7.92 (dd, 2H, J=6.5, 1.8 Hz), 7.21 (dd, 2H, J=6.4, 1.7 Hz), 3.87 (s, 3H), 2.63 (t, 2H, J=7.7 Hz), 1.60 (m, 2H), 1.38–1.06 (m, 24H), 0.86 (t, 3H, J=6.7 Hz). 13C NMR (75 MHz, CDCl3): δ 167.6, 148.9, 130.0, 128.8, 128.0, 52.3, 36.4, 32.3, 31.5, 30.09, 30.07, 30.05, 30.00. 29.95, 29.9, 29.8, 29.7, 23.1, 14.5. IR: 3091, 3061, 3031, 2925, 2854, 1726, 1611, 1574, 1510, 1466, 1435, 1415, 1377, 1309, 1277, 1191, 1178, 1109, 1021, 970, 854, 763, 722, 704 cm−1. MS m/z (rel. intensity) 332 (100, [M+]), 301 (1), 163 (34), 150 (60), 149 (29).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>ClCCl.O>[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:25]([N:24]([CH3:28])[CH3:23])=[O:26])=[CH:15][CH:14]=1)#[N:13]
Reactant: CN(C)C(=O)Cl
Reactant: N#Cc1ccc(OCCNCCO)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N(CCO)CCOc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
4-{2-[(2-Hydroxyethyl)amino]ethoxy}benzonitrile (5 g, 0.0242 mol; see Preparation C, step (ii) above) was taken in dry dichloromethane (50 mL) and cooled to 0° C. Triethylamine (4 mL, 0.03 mol), followed by N,N-dimethylcarbamoyl chloride (3.9 g, 0.03 mol), was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. Purification by column chromatography using dichloromethane in methanol yielded 6 g of the sub-title compound as pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][CH2:53][C:54]([CH3:59])([CH:56]1[CH2:58][CH2:57]1)[OH:55]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:52][CH2:53][C:54]([CH:56]1[CH2:58][CH2:57]1)([OH:55])[CH3:59])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: CC(O)(CN)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.2 %

Procedure:
5-Bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (1.1 g, 3.0 mmol) was dissolved in DMF (25 mL). To the solution was added TBTU (1.06 g, 3.3 mmol), N,N-diisopropylethyl amine (2.54 mL, 15 mmol) and α-(aminomethyl)-α-methyl-cyclopropanemethanol (0.38 g, 3.3 mmol). The reaction mixture was stirred for 16 h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (20 mL), washed with sodium hydroxide solution (0.5 N) and brine. Organic phases were pooled, dried with MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, heptane/ethyl acetate) to give the title compound (0.38 g) as a light yellow solid, MS (ISP) 462.9, 464.9 (M−H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14](C(OC(C)(C)C)=O)[CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:39])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:28])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:39])[CH3:2]
Reactant: CCOC(=O)COc1c(C)cc(N(Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)COc1c(C)cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Reaction time: 0.5 h

Procedure:
0.360 g (0.62 mmol) of the above prepared (4-{tert-butoxycarbonyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-2,6-dimethyl-phenoxy)-acetic acid ethyl ester was dissolved in 6.25 ml of CH2Cl2 and treated dropwise with 1.59 ml of TFA (33 eq.). After additional 30 min at RT, the bulk of the solvents was removed i. V. and the residue distributed between cold NaHCO3-solution and EtOAc. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents left 0.292 g of the title compound as off-white solid which was used as such for the next step, MS: 479.4 (MH)+.
Reaction SMILES: [OH-].[K+].[N+](=[CH2:5])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[C:20]([C:22]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:23][OH:24])#[N:21]>O.C(OCC)C.C(O)C>[CH3:5][O:24][CH:23]=[C:22]([C:20]#[N:21])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=[N+]=[N-]
Reactant: N#CC(=CO)CCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: COC=C(C#N)CCCCc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3.0 grams of potassium hydroxide in 6 mL of water was placed in a commercially available diazomethane generator. Ethanol, 8 mL, was added to the generator, and the contents of the generator were slowly warmed to 60° C. to 70° C. To this was added dropwise a solution of 4.6 grams (0.021 mole) of Diazald® in a minimum amount of diethyl ether. The diazomethane generated was condensed on a cold finger and, in turn, was allowed to drip into a stirred, cooled solution of 2.5 grams (0.012 mole) of 2-cyano-6-phenyl-1-hexen-1-ol in a minimum of diethyl ether. The complete generation of diazomethane required about 30 to 45 minutes. Upon completion of the diazomethane generation, the reaction mixture was allowed to warm to ambient temperature. After this time the reaction mixture was concentrated under reduced pressure, yielding 2.4 grams of 1-methoxy-2-cyano-6-phenyl-1-hexene. The NMR spectrum was consistent with the proposed structure.