Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=O)[CH2:13]1)=[O:11].F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:31][C:32]1[S:36][C:35]([C:37]([NH:39][NH2:40])=O)=[N:34][CH:33]=1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:37]([C:35]3[S:36][C:32]([CH3:31])=[CH:33][N:34]=3)=[N:39][N:40]=[C:14]2[CH2:13]1)=[O:11]
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Reactant: Cc1cnc(C(=O)NN)s1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1cnc(-c2nnc3n2CCN(C(=O)c2ccc(Cl)c(F)c2Cl)C3)s1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (329 mg, 1.13 mmol) in dry dichloromethane (DCM) (1413 μl) was stirred at room temperature under an atmosphere of argon. Triethyloxonium tetrafluoroborate (236 mg, 1.243 mmol) was added and the mixture was stirred for 1 hour. After this time, 5-methyl-1,3-thiazole-2-carbohydrazide (I117) (224 mg, 1.425 mmol) was added and the mixture was stirred for a further 60 hours (over weekend). The solvent was removed under reduced pressure. The resulting residue was dissolved in 1-butanol (1413 μl) and the solution was heated to 110° C. for 4 hours. The solution was concentrated under reduced pressure and the residue dissolved in DCM (approx. 40 ml). The organics were washed with NaHCO3 (sat. aqueous solution approx. 20 ml), before being dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow coloured oil. The oil was chromatographed [SiO2, 0-10% MeOH in DCM] then further purified using MDAP (formic acid method) to give a white coloured solid of desired product in 74 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:3]=1[O:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1.C([Li])CCC.[CH:21](N1CCOCC1)=[O:22]>O1CCCC1>[Cl:1][C:2]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:3]=1[O:4][C:5]1[S:6][C:7]([CH:21]=[O:22])=[CH:8][N:9]=1
Reactant: O=CN1CCOCC1
Reactant: COc1ccc(Oc2nccs2)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Oc2ncc(C=O)s2)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of Example 30A (12 g, 49.9 mmol) in tetrahydrofuran (100 mL) was added butyllithium (2.5 M in hexanes, 21 mL, 52.5 mmol) drop wise over 10 minutes at −78° C. under nitrogen. The mixture was stirred at −78° C. for 1 hour, and was treated with 4-formylmorpholine (5.3 mL, 52.4 mmol) drop wise over 5 minutes. The reaction was allowed to warm to 25° C. and was stirred for 2 hours. The reaction was cooled to 0° C. and quenched with saturated NH4Cl (600 mL). The resulting mixture was extracted with ethyl acetate (2×200 mL) and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to provide 13.2 g of the title compound (98%) as a light yellow liquid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.83 (s, 3H) 7.06 (dd, J=9.19, 2.94 Hz, 1H) 7.28 (d, J=2.94 Hz, 1H) 7.57 (d, J=9.19 Hz, 1H) 8.28 (s, 1H) 9.88 (s, 1H); MS (ESI) m/z 269.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)c2)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(-c2cccc(Cl)c2)c1Cl
Temperature: 0 °C
Yield: 81.1 %

Procedure:
A mixture of 7.8 g of 5-chloro-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester and 3.0 g of potassium hydroxide in 200 ml of 3A ethanol was refluxed for four hours. The solution was poured into ice water and acidified with hydrochloric acid. The aqueous acid solution was extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated under vacuum. The residue was recrystallized from ethanol to afford 5.7 g of 5-chloro-1-(3-chlorophenyl)-1H-pyrazole-4-carboxylic acid. Yield 80%. mp=209°-211° C.
Reaction SMILES: Cl[C:2]1C=CC(C2N=C(C(C)(C)CNC)NC=2C2C=CN=CC=2)=CC=1O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:34]=[C:35]([C:44]([CH3:60])([CH3:59])[CH2:45][NH:46][C:47]([N:49]3[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][O:57][CH3:58])[CH2:51][CH2:50]3)=[O:48])[NH:36][C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[CH:29][C:28]=1[OH:61]>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:34]=[C:35]([C:44]([CH3:59])([CH3:60])[CH2:45][N:46]([CH3:2])[C:47]([N:49]3[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][O:57][CH3:58])[CH2:53][CH2:54]3)=[O:48])[NH:36][C:37]=2[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)=[CH:29][C:28]=1[OH:61]
Reactant: CNCC(C)(C)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1
Reactant: COCCN1CCN(C(=O)NCC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Product: COCCN1CCN(C(=O)N(C)CC(C)(C)c2nc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)[nH]2)CC1
Yield: 41 %

Procedure:
The title compound (170 mg, 41%) was prepared from the product of Example 52 and the product of Example 49 Step 1 using the method described in Example 49 Step 2; MS(ES+) m/e 527/529 [M+H]+.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.[CH2:15]([O:17][C:18](=[O:30])[CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH3:16]>CCOC(C)=O.C(Cl)Cl>[CH2:15]([O:17][C:18]([C:19]1[C:20](=[O:21])[S:14][C:10]2[C:11]([C:25]=1[OH:26])=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)=[O:30])[CH3:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(S)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2ccc(OC)cc2sc1=O
Temperature: 210 °C
Yield: 5.5 %

Procedure:
SnCl4 was added to a neat mixture of 3-methoxy-benzenethiol (0.91 g, 6.5 mmol) and 2-ethoxycarbonyl-malonic acid diethyl ester (2.27 g, 9.77 mmol) in a 20-mL open vial. The reaction mixture was heated in a 210° C. oil bath for 2.5 h. After cooling, the reaction mixture was subjected to silica gel chromatography (3%-50% EtOAc/CH2Cl2) to provide 4-hydroxy-7-methoxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (100 mg). MS ESI(+) m/e: 281.10 (M+1).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[O:11]=[C:7]1[NH:6][C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[N:4][C:3]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]1[C:9]#[N:10]
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: C1CNCCN1
Product: N#Cc1c(N2CCNCC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 80 mg (0.30 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 326 mg (3.80 mmol) of piperazine to give 45 mg (49% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:57][O:58][C:59]([NH:61][C@@H:62]([CH:66]([CH3:68])[CH3:67])[C:63](O)=[O:64])=[O:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:7]([CH3:9])[CH3:8])[C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3[C:63](=[O:64])[C@@H:62]([NH:61][C:59]([O:58][CH3:57])=[O:60])[CH:66]([CH3:68])[CH3:67])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6CC[C@H](C)N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Reaction time: 3 h
Yield: 51 %

Procedure:
tert-butyl(2S,4S)-2-[5-(2-{(2S,5 S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (60 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (21 mg, 0.12 mmol), HATU (36 mg, 0.095 mmol) and DMF (1.5 mL), then N-methylmorpholine (0.027 mL, 0.24 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (33 mg, 51%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[CH:26]([Cl:29])(Cl)[Cl:27].[F:30][C:31]([F:58])([F:57])[O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:42]2[CH2:46][C:45]([CH:48]=O)([CH3:47])[C:44]([C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][CH:51]=3)=[N:43]2)=[O:41])=[CH:35][CH:34]=1>C1COCC1>[F:58][C:31]([F:30])([F:57])[O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:42]2[CH2:46][C:45]([CH:47]=[C:26]([Cl:29])[Cl:27])([CH3:48])[C:44]([C:50]3[CH:51]=[CH:52][C:53]([Cl:56])=[CH:54][CH:55]=3)=[N:43]2)=[O:41])=[CH:35][CH:34]=1
Reactant: CC1(C=O)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C=C(Cl)Cl)CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To 6.5 g of triphenyl phosphine and 2.5 g of potassium t-butoxide dissolved in 75 ml of THF and cooled to -70° C. was added 3.5 g of chloroform. After stiring for 5 minutes a solution of 3.9 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-formyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide in 10 ml of THF is added and the mixture is allowed to warm to 10° C. over 1 hour. The resulting mixture is partitioned between ether and water, dried, rotovaped and chromatographed (ether/hexane) on silica gel yielding 3.1 g of N-(4-trifluoromethoxyphenyl)-3-(4-chlorophenyl)-4-(2,2-dichlorovinyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide mp 138°-141° C. NMR and IR data were consistent with the structure.
Reaction SMILES: ClC1C=CC2N=C(C)C=CC=2C=1[C:13](O)=[O:14].[NH2:16][C:17](=[N:47][OH:48])[CH2:18][CH2:19][O:20][C@H:21]1[CH2:25][CH2:24][N:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:46])[C:32]=3[NH:36][C:37](=[O:45])[CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[N:27]=2)[CH2:22]1>>[Cl:46][C:31]1[C:32]([NH:36][C:37](=[O:45])[CH2:38][CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]2)=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([N:23]1[CH2:24][CH2:25][C@H:21]([O:20][CH2:19][CH2:18][C:17]3[NH:16][C:13](=[O:14])[O:48][N:47]=3)[CH2:22]1)[CH:35]=[CH:34]2
Reactant: NC(CCO[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1)=NO
Reactant: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](OCCc4noc(=O)[nH]4)C3)ccc12

Procedure:
Prepared according to the method of Example 102 (b) using N-[2-[(3S)-3-[[3-amino-3-(hydroxyimino)propyl]oxy]-1-pyrrolidinyl]-6-chloro-5-quinolinyl]-cyclohexaneacetamide (Example 108 (a)) (200 mg). Purification (SiO2, methanol:dichloromethane 2:98 as eluant) gave the title compound as a solid (20 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16](Cl)=O.C(NC1C=CC2N=C(C3C(F)=CC=CC=3F)OC(=O)C=2C=1)(=O)C>C(N(CC)CC)C.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([F:12])[C:9]([F:11])=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CC(=O)Nc1ccc2nc(-c3c(F)cccc3F)oc(=O)c2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2F)nc2cc(F)c(F)cc12

Procedure:
2-Amino-4,5-difluorobenzoic acid (0.5 g), 2,6-difluorobenzoyl chloride (0.80 mL) and triethyl amine/toluene (1/1) (18 mL) were reacted as described under (10). Reaction time 1 day. Extraction between ethyl acetate (20 mL) and HCl (2N,20 mL), followed by separation of the organic toluene and precipitated with hexane. The resulting mixture was further purified on a silicagel column using dichloromethane as eluent. The isolated fraction identified as 2-(2,6-difluoro-phenyl)-6,7-difluoro-benzo[d][1,3]oxazin-4-one (0.71 g), mp. 165 C, MS m/e: 295 M+.
Reaction SMILES: [N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:15])=O>ClCCl>[N+:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]([Cl:15])=[O:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1csc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1csc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-nitro-thiophene-3-carboxylic acid (5.0 g, 29 mmol) in dichloromethane (60 ml) was added oxalyl chloride (2.93 ml, 35 mmol) at room temperature. The mixture was stirred for 30 minutes at room temperature then for 30 minutes at 50° C. The solvent was evaporated and the residue suspended in tetrahydrofuran (30 ml). The solution was used without purification in the next step.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+]([O:24][N:25]1N=NC2C=CC=C[C:26]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41]N1CCOCC1>C(#N)C.CCOC(C)=O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[N:25]([O:24][CH3:41])[CH3:26])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CON(C)C(=O)CCNC(=O)OC(C)(C)C

Procedure:
A solution of BOC-beta-alanine (20 g, 105 mmol), 10-2 (10.3 g, 105 mmol), BOP reagent (46.5 g, 105 mmol), and N-methylmorpholine (46 mL, 420 mmol) in acetonitrile (500 mL) was stirred for 15 h. The reaction was diluted with EtOAc, washed with H2O, 10% KHSO4 (aq.), sat. NaHCO3, dried (MgSO4) and concentrated to give crude [2-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester 10-3 as a yellow oil. TLC Rf =0.42 (silica, 20% EtOAc/hexanes). To a solution of this crude amide in THF (500 mL) at 0° C. was added CH3MgBr (100 mL of 3M in ether, 300 mmol) over 30 minutes. After 2 h, 10% KHSO4 (aq.) was added, the mixture warmed to 25° C., and diluted with EtOAc. The organics were washed with sat. NaHCO3, dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 10-4 as a yellow oil.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([C:8]1[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=1)=[O:7].FC(F)(F)C(O)=O>ClCCl>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:9]=[C:8]2[C:6](=[O:7])[NH:5][CH:4]=[CH:3][N:12]2[N:11]=1
Reactant: COC(CNC(=O)c1cc(C(F)(F)F)n[nH]1)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]ccn2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 267 mg (1 mmol) of N-(2,2-dimethoxyethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, 1.6 mL of trifluoroacetic acid, and 1.6 mL of dichloromethane was stirred at room temperature overnight and then concentrated. The residue was suspended in polyphosphoric acid (enough to cover it) and heated at 145° C. for 4.5 h. The cooled mixture was treated with ice, and the pH was adjusted to 8-9 by addition of concentrated ammonium hydroxide solution. The mixture was transferred to a separatory funnel and shaken with dichloromethane. The organic phase was separated, and the aqueous phase was extracted twice more with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to yield the title compound as a solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].Cl>C(O)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:20][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Reactant: CCCCN
Agent: Cl
Solvent: CCO
Product: CCCCNCCOc1cc(F)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.3 g, 1.01 mmol) and butan-1-amine 0.61 ml, 0.5907 mmol) in ethanol (4 ml). Yield: 290 mg (99%). The amine was converted to the hydrochloric acid salt and re-crystallized from ethanol/diethyl ether: M.p. 204° C. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 246 (35), 86 (bp), 56 (12), 87 (12).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][CH:13]=1)=O)(C)(C)C.C([NH:27][C:28]([NH:30][C:31]([C:33]1[C:38]([NH2:39])=[N:37][C:36]([NH2:40])=[C:35]([Cl:41])[N:34]=1)=[O:32])=N)CCC>>[ClH:41].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:28]([NH:30][C:31]([C:33]2[C:38]([NH2:39])=[N:37][C:36]([NH2:40])=[C:35]([Cl:41])[N:34]=2)=[O:32])=[NH:27])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(CCCCN)cc1
Reactant: CCCCNC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Product: Cl
Product: N=C(NCCCCc1ccc(OCCN)cc1)NC(=O)c1nc(Cl)c(N)nc1N

Procedure:
Using general procedure Z, 4-[4-(2{t-butoxycarbonylamino}ethyloxy)phenyl]butyl amine was converted into 4-[4-(2-{t-butoxycarbonylamino}ethyloxy)phenyl)]butylamidino-3,5-diamino-6-chloropyrazinecarboxamide, m.p. 118° C., APCI MS M/Z=521[C23H33ClN8O4+H]+, which was hydrolyzed and acidified with HCL to give 4-[4-(2-aminoethyloxy)phenyl)butylamidino-3,5-diamino-6-chloropyrazinecarboxamide hydrochloride, m.p.>178° C. (dec), M/Z=421 [C18H25ClN8O2].
Reaction SMILES: COC(=O)[NH:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[O:22])[NH:20][CH3:21])[CH:14]=3)[CH:10]=[N:9][N:8]2[C:23]=1Br.[Cl:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:4][C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:19]([NH:20][CH3:21])=[O:22])[CH:10]=[N:9][N:8]2[C:23]=1[C:31]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:26])[CH:32]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CNC(=O)c1cccc(-c2cnn3c(Br)c(NC(=O)OC)nc3c2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2cnn3c(-c4ccnc(Cl)c4)c(N)nc3c2)c1

Procedure:
[3-Bromo-7-(3-Methylcarbamoyl-phenyl)-imidazo-[1,2-b]-pyridazin-2-yl]-carbamic acid methyl ester (1 eq, 0.159 mmol, 65 mg) and 2-chloropyridine-4-boronic acid (1.2 eq, 0.191 mmol, 30.1 mg) are dissolved in DME (3 ml) and water (0.75 ml) and Na2CO3 (3 eq, 0.478 mmol, 50.6 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.008 mmol, 5.59 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 50 min. At the completion of this time the solvent is evaporated and the reaction mixture is dissolved in MeOH, filtered and the solvent is removed in vacuo to yield 3-[2-Amino-3-(2-Chloro-pyridin-4-yl)-imidazo -[1,2-b]-pyridazin-7-yl]-N-methyl benzamide as a yellow solid; [M+H]+=379
Reaction SMILES: S1C2C(O)=CC=CC=2C=N1.[F:11][C:12]1[C:20]2[S:19][N:18]=[CH:17][C:16]=2[C:15]([O:21]C)=[CH:14][CH:13]=1.Cl.N1C=CC=CC=1>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([OH:21])=[C:16]2[C:20]=1[S:19][N:18]=[CH:17]2
Reactant: COc1ccc(F)c2sncc12
Agent: Cl
Agent: Oc1cccc2cnsc12
Solvent: c1ccncc1
Product: Oc1ccc(F)c2sncc12
Yield: 9.1 %

Procedure:
A method similar to that described for the synthesis of benzo[d]isothiazol-7-ol in WO 04/043904 was used from 7-fluoro-4-methoxybenzo[d]isothiazole (500 mg, 27.32 mmol) and pyridine hydrochloride (2.5 g, 21.74 mmol) to give the title compound as grey solid (420 mg, 65%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[C:8]([CH3:14])[CH:7]=2)[CH2:3][CH2:2]1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH3:12])=[CH:10][C:9]([N:13]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:8]([CH3:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(OCC2CC2)c(C)cc1N
Product: Cc1cc(OCC2CC2)c(C)cc1N=CN(C)C

Procedure:
A mixture of 0.23 g of 4-cyclopropylmethoxy-2,5-dimethylphenylamine and 10 mL of N,N-dimethylformamide dimethylacetal was stirred under heating and refluxing for 10 hours. The cooled reaction mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.18 g of N′-(4-cyclopropylmethoxy-2,5-dimethylphenyl)-N,N-dimethylformamidine (Compound of Present Invention (1-17)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([OH:16])([C:14]#[CH:15])[CH3:13].CS(C)=O.[OH-].[K+]>>[C:4]([C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[O:16][C:12]([CH3:13])([CH3:11])[C:14]#[CH:15])#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: C#CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C#CC(C)(C)Oc1cccc(F)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a stirred solution of 108.3 grams (0.78 mole) of 2,6-difluorobenzonitrile and 78.2 grams (0.93 mole) of 2-methyl-3-butyn-2-ol in 800 mL of dimethyl sulfoxide 65.5 grams (1.17 moles) of potassium hydroxide was added portionwise during a 20 minute period. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about 18 hours, after which the reaction mixture was poured into ice-water and extracted with diethyl ether. The extract was washed with water and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure, yielding 75.3 grams of 3-(2-cyano-3-fluoro-phenoxy)-3-methyl-1-butyne. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH2:13][CH:14]([OH:17])[CH2:15][NH2:16])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C.[Pd]>[CH2:20]([NH:16][CH2:15][CH:14]([OH:17])[CH2:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:19][CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCC(O)COc1ccc(CCOCC2CC2)cc1
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OC(CNCc1ccccc1)COc1ccc(CCOCC2CC2)cc1

Procedure:
In an alternative method, 3-[4-(2-(cyclopropylmethoxy)ethyl)phenoxy]-2-hydroxypropylamine (1.33 g), (see Example 5 (i) in ethanol (20 ml) was stirred at room temperature whilst a solution of benzaldehyde (1.06 g) in ethanol (20 ml) was added. The mixture was poured on to a slurry of 5% palladium on charcoal (0.5 g) in ethanol (5 ml) and hydrogenated at 344 kPa (50 p.s.i.) for 10 minutes. The mixture was filtered through diatomaceous earth and the filtrate evaporated to give a clear oil which crystallised on standing to give N-benzyl-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2-hydroxypropylamine, in quantitative yield, identical to an authentic sample by chromatography and a nuclear magnetic resonance spectrum.