Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CN(C)C=O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: C1CNCCNC1
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCCNCC1
Reaction time: 4 h
Yield: 13.7 %

Procedure:
Ethyl bromoacetate (3.7 g, 18.4 mmol, Aldrich) was added in portions to a solution of homopiperazine (2.76 g, 27.6 mmol, Avocado) in N,N-dimethylformamide (15 mL) at room temperature over 1.5 h. The mixture was then stirred for additional 4 h followed by an aqueous workup. The crude was purified by column flash chromatography to give homopiperazine-acetic acid ethyl ester (471 mg).
Reaction SMILES: [C:1]([C:3]1[C:9]([F:10])=[CH:8][C:6]([NH2:7])=[C:5]([F:11])[CH:4]=1)#[N:2].[C:12](Cl)(Cl)=[S:13]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:9]([F:10])=[CH:8][C:6]([N:7]=[C:12]=[S:13])=[C:5]([F:11])[CH:4]=1)#[N:2]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1cc(F)c(N)cc1F
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)c(N=C=S)cc1F

Procedure:
10.0 g (65 mmol) of 4-cyano-2,5-difluoro-aniline are introduced into 100 ml of toluene and 8.2 g (71 mmol) of thiophosgene are slowly added to the mixture heated to 80° C. to 90° C. The reaction mixture is then refluxed for approximately 40 hours. Then, after the solvent has been carefully distilled off under reduced pressure, the product (4-cyano-2,5-difluoro-phenyl isothiocyanate) is obtained as an ochre colourant.
Reaction SMILES: [Cl:1][C:2]1[C:12]([NH2:13])=[C:6]2[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]2=[C:4]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:15]=2)[CH:3]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(N(CC)CC)C>CN(C)C=O>[NH2:13][C:12]1[C:6]2[CH2:7][C:8]([CH3:10])([CH3:11])[O:9][C:5]=2[C:4]([C:14]2[O:18][N:17]=[C:16]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:26][CH2:27][CH2:28][C:29]#[N:30])[CH2:23][CH2:24]3)[N:15]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: CC1(C)Cc2c(N)c(Cl)cc(-c3nc(C4CCNCC4)no3)c2O1
Reactant: N#CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(N)c(Cl)cc(-c3nc(C4CCN(CCCC#N)CC4)no3)c2O1
Temperature: 70 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of intermediate 5 (4 g), 4-bromobutanenitrile (2.2 g) and triethylamine (4.2 ml) in dimethylformamide (70 ml) was stirred for 2 hours at 70° C. The mixture was cooled and the solvent evaporated. The residue was partitioned between CH2Cl2 and NH3 /H2O. The organic layer was separated, dried over MgSO4, filtered and the solvent evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated. The residue was solidified in DIPE at 0° C., filtered and dried, yielding 1.89 g (38%) of 4-[5-(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)-1,2,4-oxadiazol-3-yl]-1-piperidinebutanenitrile (compound 3; mp. 151.4° C.).
Reaction SMILES: [C:1]([C@@H:4]([O:12][C:13](=[O:44])[CH2:14][C@H:15]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:16]([CH3:35])([CH3:34])[C:17](=[O:33])[C@H:18]([CH3:32])[C@@H:19]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[C@@H](C)C=C)[CH2:5]/[CH:6]=C(/C)\CC=C)(=[O:3])[CH3:2].[C:45]1([CH3:51])[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:1]([C@H:4]1[O:12][C:13](=[O:44])[CH2:14][C@H:15]([O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:39])[CH3:38])[C:16]([CH3:34])([CH3:35])[C:17](=[O:33])[C@H:18]([CH3:32])[C@@H:19]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:26])[CH3:27])[C@@H:45]([CH3:51])[CH:50]=[CH:49][CH2:48][C:47]([CH3:46])=[CH:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1
Reactant: C=CC/C(C)=C\C[C@H](OC(=O)C[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)C(=O)[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C=C)C(C)=O
Agent: CC(=O)[C@@H]1C/C=C(/C)C/C=C/[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CC(=O)[C@@H]1CC=C(C)CC=C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reaction time: 0.5 h

Procedure:
A solution of 50.0 mg (76.8 μmol) of (3S,6R,7S,8S)-3,7-bis-(tert-butyl-dimethyl-silanyloxy)-4,4,6,8-tetramethyl-5-oxo-dec-9-enoic acid (Z)-(S)-1-acetyl-4-methyl-hepta-3,6-dienyl ester in 200 ml toluene was heated at reflux. 10.8 mg (11.5 μmol) of [RuCl2(PCy3)(ImH2Mes)(3-phenyl-indenylidene)] was added and the resulting yellowish solution stirred at reflux. After 30 min, a 50 ml sample was evaporated to dryness and to remove residual toluene, redissolved in 25 ml ethanol and evaporated to dryness to yield the title compound with 80% purity (HPLC method described in Example 4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][C:24]=2[C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[N:21][C:22]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[C:37]([F:38])[CH:36]=3)=[CH:23][C:24]=2[C:25]2[CH:29]=[N:28][NH:27][CH:26]=2)=[CH:4][C:5]([F:17])=[C:6]([S:8]([NH:11][C:12]2[N:13]=[CH:14][S:15][CH:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cn[nH]c2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3ccc(F)c(F)c3)cc2-c2cn[nH]c2)cc1F
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
15.0 mg (0.03 mmol) of 5-chloro-4-((6-chloro-4-(1H-pyrazol-4-yl)pyridin-3-yl)oxy)-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide was dissolved in 1.5 mL of 1,4-dioxane, and 7.1 mg (0.05 mmol) of (3,4-difluorophenyl)boronic acid was added thereto, and then 3.5 mg (10 mol %) of Pd(PPh3)4, 12.4 mg (0.09 mmol) of K2CO3, and 0.3 mL of H2O were added thereto. After reacting with microwave reactor at 150° C. for 30 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, dimethylchloride:methanol=20:1) to obtain 9.0 mg (31.9% yield) of the title compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:41]
Reactant: O=C(Cl)CCCCCl
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CCCCCl)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (200 mg, 0.486 mmol) was dissolved in dichloromethane (3 ml) and triethylamine (203 μl, 1.46 mmol) was added followed by dropwise addition of 5-chlorovaleryl chloride (69 μl, 0.535 mmol). The reaction was stirred under nitrogen at room temperature for 2 h. The reaction mixture was quenched with sat. sodium hydrogen carbonate solution (5 ml) and extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure to give the title compound (259 mg) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH:17](Br)Br)=[CH:13][C:12]=2[F:20])[S:6]1(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2].C([OH:25])C>O.[N+]([O-])([O-])=O.[Ag+]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:25])=[CH:13][C:12]=2[F:20])[S:6]1(=[O:22])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)N1C(=O)CC(c2ccc(C(Br)Br)cc2F)S1(=O)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC(C)(C)N1C(=O)CC(c2ccc(C=O)cc2F)S1(=O)=O
Temperature: 25 °C
Yield: 83 %

Procedure:
2-tert-Butyl-5-[4-(dibromomethyl)-2-fluorophenyl]isothiazolidin-3-one 1,1-dioxide (4.2 g, 9.2 mmol) and silver nitrate (3.12 g, 18.4 mmol) in ethanol (200 mL) and water (50 mL) were heated at reflux for 0.5 h. The solution was cooled to rt, filtered to remove precipitate, and concentrated to remove most of the ethanol. The residue was diluted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL) and then dried over sodium sulfate. Concentration in vacuo followed by purification by silica gel chromatography (30% ethyl acetate:hexanes) afforded product as a white solid (2.4 g, 83%). 1H NMR (400 MHz, CDCl3): δ 10.0 (d, J=2.0 Hz, 1H), 7.78–7.75 (m,1H), 7.70–7.65 (m, 1H), 7.56–7.52 (m, 1H), 5.13 (dd, J=8.9, 6.6 Hz, 1H), 3.35 (dd, J=17.2, 8.9 Hz, 1H), 3.15 (dd, J=17.2, 6.6 Hz, 1H), 1.66 (s, 9H). LCMS found for C14H17FNNaO4S (M+Na)+: m/z=336.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:19][CH2:20][CH3:21])=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:22].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:31][NH:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:10]3[CH:9]=[C:8]([CH2:19][CH2:20][CH3:21])[C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:22])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:25][CH:26]=1
Reactant: CCCc1cc(CN2CCNCC2)cc2c1OC(C)C(=O)N2
Reactant: CNC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1cc(CN2CCN(c3ccc(C(=O)NC)cc3)CC2)cc2c1OC(C)C(=O)N2
Temperature: 120 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
In a 20 mL scintillation vial was added 2-methyl-6-(piperazin-1-ylmethyl)-8-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one 358E (67 mg, 0.221 mmol) and 4-fluoro-N-methylbenzamide (50.7 mg, 0.331 mmol) in DMSO (1.104 mL) and stirred at 120° C. for 4 h. DBU (0.133 mL, 0.883 mmol) was added and the reaction mixture was stirred at 120° C. for 18 h. The reaction was concentrated in vacuo to remove DBU, and then K2CO3 (61.0 mg, 0.442 mmol) was added. The mixture was heated overnight at 120° C. The reaction was subsequently filtered and the crude material was purified by prep HPLC 20-45% acetonitrile in water. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (18 mg, 0.041 mmol, 18.67% yield). 1H NMR (DMSO-d6, 400 MHz): δ=10.89 (s, 1H), 10.73 (br. s., 1H), 8.04 (br. s., 1H), 7.75 (d, J=8.8 Hz, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.95-7.04 (m, 2H), 6.87 (d, J=2.0 Hz, 1H), 4.66-4.72 (m, 1H), 4.64 (d, J=6.6 Hz, 2H), 3.26 (t, J=7.1 Hz, 2H), 3.03 (q, J=6.7 Hz, 2H), 2.30-2.45 (m, 3H), 1.61-1.67 (m, 2H), 1.55 (d, J=6.8 Hz, 5H), 1.40 (d, J=6.8 Hz, 3H), 0.86-0.93 ppm (m, 3H). ESI-MS: m/z 437.4 (M+H)+.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][O:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([Br:3])=[CH:5][C:6]=1[F:12]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(F)cc(Br)cc1F
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Methyl iodide (17.11 g, 0.12 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2,6-difluorophenol (21 g, 0.1 mol; see step (i) above) and K2CO3 (27.78 g, 0.2 mol) in dry acetone (150 mL). Stirring was continued at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered, the solvent was evaporated and the residue was purified by column chromatography over silica gel, using petroleum ether as eluent, to give 11.5 g of the sub-title compound as a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:11]([NH:13][CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)([OH:20])[C:16]([F:19])([F:18])[F:17])[CH3:12]>>[CH2:11]([N:13]([CH2:14][C:15]([CH2:21][NH:22][C:23]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][N:27]2[C:33]1[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=1)([OH:20])[C:16]([F:18])([F:19])[F:17])[C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])[CH3:12]
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1F

Procedure:
Prepared similarly to Example 1 from 2-fluorobenzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:14]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C
Yield: 98 %

Procedure:
(L)-tert-Leucine (10 g, 0.076 mol) was dissolved in 1,4-dioxane (40 mL) and treated with 2M NaOH (125 mL, 3.2 equivalents) followed by dropwise addition of methyl chloroformate (11.2 mL, 1.9 equivalents) at 25° C. The mixture was heated at 60° C. for 22 hrs, cooled, and extracted twice with dichloromethane. The aqueous layer was separated, cooled in ice bath, and acidified with 4N HCl (60 mL). The mixture was extracted three times with ethyl acetate, and the organic layer was separated, dried with sodium sulfate, filtered, and the solvents were evaporated to give 14.1 g (98%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].Cl.[H][H]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:14][NH:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)(F)F)c(F)c2)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COC(=O)C1CNCC(c2ccc(OC(F)(F)F)c(F)c2)C1

Procedure:
A solution of 5.73 g (18.2 mmol) of the compound from Example 91A in 116 ml of ethanol was admixed with 1.11 g (0.27 mmol) of platinum oxide, and hydrogenated with 14.3 ml of concentrated hydrochloric acid solution and at RT overnight in a 3.5 bar hydrogen atmosphere. The catalyst was then filtered off through a filter layer and washed repeatedly with ethanol. The combined filtrates were concentrated under reduced pressure. Yield: 5.95 g (100% of theory)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([N:14]=[C:15]=[S:16])[CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:17])=[C:12]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:13]=1
Reactant: Cc1ccc(F)cc1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(F)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.8 %

Procedure:
A mixture of glycinamide hydrochloride (4.42 g), 5-fluoro-2-methylphenyl-isothiocyanate (6.68 g), triethyl amine (4.1 g), and chloroform (150 mL) was stirred at ambient temperature for 18 hours. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(5-Fluoro-2-methylphenyl)-thioureido]-acetamide (7.6 g), m.p. 172°-174° C. (dec.). This compound was used without further purification in the next paragraph.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:28][C:29]1[C:30]([F:37])=[C:31]([NH:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[C:30]([F:37])=[C:31]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NNc1cccc(Cl)c1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(S(=O)(=O)C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-33) and 3-chloro-2-fluoro-phenylhydrazine according to the method described for example 1. MS: M=499.0 (M+H)+
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(OCC)(=O)C>[CH2:10]([NH:13][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:11][CH3:12]
Reactant: CCCN
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1ccccc1
Yield: 96 %

Procedure:
Benzoyl chloride (10 mL, 86.2 mmol) in ethyl acetate (200 mL) was treated with propylamine. The precipitate was removed by filtration, and the solution was washed with 1M HCl, 5% NaHCO3, and brine, dried over MgSO4 and concentrated in vacuo to give the title compound in 96% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:23][CH:24]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester prepared in Step C of Preparation 20, (0.497 g, 2.09 mmol) in MeOH (8 mL) was added 4-tert-butylbenzaldehyde (0.33 mL, 1.97 mmol), and the mixture was stirred at room temperature for 2 h. The solution was cooled to 0° C. and sodium borohydride (0.119 g, 3.15 mmol) was added in one portion. The mixture was stirred for 10 min, and a 1:1 solution of water:aqueous saturated sodium bicarbonate was added to the solution. The product was extracted into CH2Cl2 (3×) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. The product was purified via silica gel chromatography (EtOAc followed by 5% MeOH in CH2Cl2) to give the title compound of Step A (0.691 g) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.30-7.38 (m, 2H), 7.19-7.28 (m, 3H), 6.87-6.96 (m, 2H), 6.77 (d, 1H), 4.50 (s, 2H), 3.77 (s, 2H), 3.75 (s, 2H), 1.46 (s, 9H), 1.30 (s, 9H); MS 384 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[C:8]([C:14]([NH2:16])=O)=[N:9][C:10]([I:13])=[CH:11][N:12]=1.O.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[C:14]([C:8]1[C:7]([N:6]=[CH:18][N:19]([CH3:22])[CH3:20])=[N:12][CH:11]=[C:10]([I:13])[N:9]=1)#[N:16]
Reactant: CN(C)C=O
Reactant: NC(=O)c1nc(I)cnc1N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=Nc1ncc(I)nc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0° C. to 11 g (41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with 1 N soda solution; a precipitate is formed. The mixture is allowed to gradually return to room temperature and then the solid formed is filtered, rinsed with water and dried at 50° C. to yield 10.50 g of N′-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[CH3:28])=[O:6].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[C:32]([NH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([OH:20])[C:16]([F:17])([F:18])[F:19])=[CH:10][C:9]=1[CH3:28])=[O:6])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(O)(c2ccc(F)cc2)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-amino-N-{2,6-dimethyl-4-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-1-hydroxy-ethyl]-phenyl}-benzamide (0.064 g, 0.15 mmol) (Example I4) in absolute dichloromethane (2 ml), at 20° C., was added a solution of benzoyl chloride (0.021 g, 0.15 mmol) in dichloromethane (0.5 ml). After 10 minutes, the suspension was treated with a solution of pyridine (0.016 g, 0.2 mmol) in dichloromethane (0.5 ml). The solution was stirred at 20° C. for 2 hours. The reaction mixture was quenched by addition of water (2 ml) and a few drops of aqueous hydrochloric acid (1M). The phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were dried over sodium sulfate, filtered through a plug silica gel which was further washed with ethyl acetate and concentrated. The residue was triturated in hexanes, filtered, washed with pentane and dried to yield the title compound as colorless crystals.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[C:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:46]=[CH:47][C:42]([C:40]#[N:41])=[CH:43][CH:44]=2)[CH2:53][CH2:52]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc(C2CCC(=O)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2CCC(=CCC3OCCCO3)CC2)cc1
Yield: 56 %

Procedure:
Into a three-necked flask equipped with a dropping funnel, a three-way cock and a thermometer, was placed 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (12.2 g, 27 mmols), followed by adding tetrahydrofuran (200 ml), suspending, stirring the suspension under ice cooling till the liquid temperature reached 10° C., adding to the reaction mixture, potassium t-butoxide (30 g, 27 mmols), elevating the temperature up to room temperature under ice cooling for one hour, stirring the mixture for one hour, dropwise adding a tetrahydrofuran (50 ml) solution of 4-(4-cyanophenyl)cyclohexanone (5.0 g, 25 mmols) from the dropping funnel over 30 minutes. The reaction mixture was stirred for 5 hours after completion of the dropwise addition, followed by adding ether (100 ml), allowing the mixture to stand, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure, and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain 1-(2-(1,3-dioxan-2-yl)ethylidene)-4-(4-cyanophenyl)cyclohexane (4.1 g, 14 mmols).