Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.[NH2:25][C:26]1[CH:31]=[C:30](Br)[CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N>[Cu](I)I.O.O1CCOCC1>[NH2:25][C:26]1[CH:31]=[C:30]([NH:14][C:12]([C:10]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]3=[N:7][CH:8]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=[C:5]3[CH:11]=2)=[O:13])[CH:29]=[CH:28][N:27]=1
Reactant: Nc1cc(Br)ccn1
Reactant: NC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(NC(=O)c2cc3cc(C(F)(F)F)cnc3n2Cc2cccc(F)c2)ccn1
Temperature: 170 °C
Yield: 86.8 %

Procedure:
0.056 g (0.30 mmol) of copper iodide, 0.2 g (0.59 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, prepared according to the protocol described in step 15.1, 0.11 g (0.65 mmol) of 2-amino-4-bromopyridine, 0.33 g (2.37 mmol) of potassium carbonate and 5 mL of anhydrous dioxane are placed in a 10 mL pressure tube specific for microwave reactors. The suspension is degassed for a few minutes and 0.04 mL (0.33 mmol) of trans-1,2-cyclohexanediamine is then added. The tube is then sealed and heated in the microwave reactor at 170° C. for 45 minutes. After this time, the suspension cooled to room temperature is poured into 30 mL of water and then extracted with 2×40 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. 0.22 g of the expected product is thus obtained in the form of a white solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1>>[O:43]1[C:44]2[CH:45]=[CH:46][C:38]([CH2:37][NH:47][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([CH3:34])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:39][C:40]=2[O:41][CH2:42]1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1ccc2c(c1)OCO2
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc5c(c4)OCO5)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and piperonylamine, m.p. 149-151° C. MS [(+)ESI, m/z]: 568 [M+H]+ Anal. Calcd for C36H31N3O4: C, 75.90; H, 5.49; N, 7.38. Found: C, 75.77; H, 5.36; N, 7.19.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][CH2:16][CH2:17][C@@H:18]1[CH2:24][N:23]([CH3:25])[C:22](=O)[C:21]2[CH:27]=[CH:28][CH:29]=[N:30][C:20]=2[O:19]1.C1(C)C=CC=CC=1>C(#N)C>[Cl:15][CH2:16][CH2:17][C@@H:18]1[CH2:24][N:23]([CH3:25])[C:22](=[S:2])[C:21]2[CH:27]=[CH:28][CH:29]=[N:30][C:20]=2[O:19]1
Reactant: CN1C[C@@H](CCCl)Oc2ncccc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1C[C@@H](CCCl)Oc2ncccc2C1=S

Procedure:
To a suspension of 9 g (0.02 mole) of phosphorus pentasulfide in 75 ml of acetonitrile was added 18 g (0.075 mole) of (R)-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepine-5(4H)-one and the mixture was stirred at reflux for 2.5 hr, cooled and treated with 60 ml of toluene. The mixture was filtered and the solid washed twice with 30 ml of 25% acetonitrile-75% toluene. The volume was made to about 400 ml with 50% toluene-50% acetonitrile and extracted with saturated aqueous potassium bicarbonate. The organic layer was separated, treated with magnesium sulfate and charcoal, and filtered. The filtrate was concentrated and the residue was recrystallized from isopropyl alcohol-chloroform. Yield of title compound was 13 g (68%), m.p. 168°-170° C.; [α]D25 =(-) 47.4 (chloroform).
Reaction SMILES: [OH:1][C@:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=O)[CH:5]=[CH:4][C:3]1=2.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:1][C@:2]1([C:15]2[S:16][C:17]([C:20]3[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([NH:27][C:28]4[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][N:29]=4)[N:21]=3)=[CH:18][N:19]=2)[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:14])[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc([C@@]3(O)CCCc4cc(C(=O)O)ccc43)s2)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc([C@@]3(O)CCCc4cc(C(=O)NS(C)(=O)=O)ccc43)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
To a suspension of (R)-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (20 mg, 0.038 mmol) and methanesulfonamide (4.34 mg, 0.046 mmol) in DCM (2 mL) at rt was added HATU (28.9 mg, 0.076 mmol) followed by Hunig's base (0.040 mL, 0.228 mmol) and the mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure, and the residue was purified by reverse phase HPLC using a C18 column and a solvent system of MeCN and water modified with 0.1% TFA. The product-containing fractions were collected and lyophilized to give (R)-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-N-(methylsulfonyl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide (22.4 mg, 82%) as light yellow solid. MS ESI calcd for C27H24F3N5O4S2 [M+H]+ 604, found 604. 1H NMR (500 MHz, dmso) δ 10.21 (s, 1H), 8.65 (s, 1H), 8.48 (s, 1H), 8.22 (d, J=3.9, 1H), 7.74 (s, 1H), 7.69-7.61 (m, 1H), 7.39-7.29 (m, 2H), 7.26-7.17 (m, 1H), 7.10 (s, 1H), 3.34 (s, 3H), 2.87 (m, 2H), 2.40-2.32 (m, 2H), 2.30 (s, 3H), 2.17-2.06 (m, 1H), 2.05-1.88 (m, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[S:23][C:22]([NH:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)=[N:21][C:20]=3[NH2:44])[O:16][N:15]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)=O.C(OCC)C>[C:1]([O:5][C:6](=[O:45])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:18]=[C:17]([C:19]3[S:23][C:22]([NH2:24])=[N:21][C:20]=3[NH2:44])[O:16][N:15]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2noc(-c3sc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N)n2)c1
Solvent: O=CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cccc(-c2noc(-c3sc(N)nc3N)n2)c1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A solution of 1.3 mmol of (3-{5-[4-amino-2-(trityl-amino)-thiazol-5-yl]-[1,2,4]oxadiazol-3-yl}-phenyl)-carbamic acid tert-butyl ester, prepared as described in Example B(1), dissolved in 8 ml of 1:1 formic acid/diethyl ether was stirred at room temperature until the starting material had been consumed by TLC (typically 5 h). The resulting light yellow solution was stripped of all solvent in vacuo, heated gently under high vacuum to remove residual formic acid, and then recrystallized from methylene chloride, giving 255 mg of the title compound (53% yield) as a light-yellow powder.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[C:13]([CH2:17][C:18]([NH2:20])=O)[CH:14]=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC.Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][NH2:20])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CC(N)=O)c2)n1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)n(-c2cccc(CCN)c2)n1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
To a stirred solution of Example N (2 g, 7.35 mmol) in THF (6 ml) was added borane-methylsulfide (18 mmol). The mixture was heated to reflux for 90 min and cooled to RT, after which 6N HCl was added and heated to reflux for 10 min. The mixture was basified with NaOH and extracted with EtOAc. The organic layer was dried (Na2SO4) filtered and concentrated in vacuo to yield 3-tert-butyl-1-[3-(2-aminoethyl)phenyl]-1H-pyrazol-5 amine (0.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH2:12][CH:13]([CH3:15])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)CBr
Reactant: OCc1ccc(Cl)cc1O
Product: CC(C)COc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and 1-bromo-2-methylpropane according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 1.04 (6H, d, J=6.8 Hz), 2.07-2.17 (1H, m), 2.29 (1H, s), 3.75 (2H, d, J=6.4 Hz), 4.65 (2H, d, J=4.8 Hz), 6.83 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.20 (1H, d, J=8.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][N:13]=[N:12][C:11]2([CH3:18])[N+]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.[OH-].[K+].C(O)C>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH3:18])=[N:12][NH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2CN=NC2(C)[N+](=O)[O-])cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c[nH]nc2C)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
A mixture of 4-(3-bromo-4-methoxyphenyl)-3-methyl-3-nitro-4,5-dihydro-3H-pyrazole (100 mg, 0.32 mmol) and 0.5 mL of water was stirred at room temperature and 2.0 mL of 40% aqueous potassium hydroxide was added. After the mixture had been sonicated for 5 min, 1.0 mL of 95% ethanol was added, followed 20 min later by another 0.5 mL of 95% ethanol. After 15 min, the solution was extracted with 2×20 mL of ether. The ether extracts were washed in succession with 10 mL of saturated aqueous sodium chloride solution, dried (sodium sulfate), decanted, and evaporated to give a white solid. Flash column chromatography on 4 g of silica gel eluting with 15-20% ethyl acetate in dichloromethane gave 80 mg of white solid (94% yield). 1H NMR (400 MHz, CDCl3): δ 7.62 (s, 1H), 7.30 (dd, 1H, J=8, 2 Hz), 6.94 (d, 1H, J=8 Hz), 3.93 (s, 3H), 2,43 (s, 3H). Mass spectrum (NH3CI): m/e=267 (M+1).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([CH3:14])[N:8]=1.Br[C:16]1[CH:21]=[C:20]([N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[CH:19]=[CH:18][N:17]=1>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[F:13][C:12]1[C:7]([C:18]2[CH:19]=[C:20]([N:22]3[C:23](=[O:32])[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]3=[O:31])[CH:21]=[CH:16][N:17]=2)=[N:8][C:9]([CH3:14])=[CH:10][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccnc(Br)c1
Reactant: Cc1ccc(F)c(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)c(-c2cc(N3C(=O)c4ccccc4C3=O)ccn2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
Tetrahydrofuran (10 mL) was cooled to −78° C. and tert-Butyllithium (4.56 ml, 6.84 mmol) was added, followed by a solution of 2-bromo-3-fluoro-6-methylpyridine (1 g, 5.26 mmol) in tetrahydrofuran (2.5 mL). The reaction mixture was stirred for 30 minutes then zinc(II)chloride (2.58 g, 18.95 mmol) was added and the reaction was warmed to room temperature over 2 hours. A solution of 2-(2-bromopyridin-4-yl) isoindoline-1,3-dione (9) (1.595 g, 5.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.608 g, 0.526 mmol) in THF (10 mL) was added and the reaction was stirred at room temperature over night to give a solid which was collected by filtration to give 2-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)isoindoline-1,3-dione as a white solid (786 mg).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][C:29]2[CH:30]=[CH:31][C:32]3[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]4[CH2:43][CH2:42]4)=[O:40])[N:37]=3)[N:34]=2)=[CH:26][CH:25]=1>CN(C)C(=O)C.O1CCCC1>[C:1]1(/[CH:7]=[CH:8]/[C:9]([NH:23][C:24]2[CH:45]=[CH:44][C:27]([O:28][C:29]3[CH:30]=[CH:31][C:32]4[N:33]([CH:35]=[C:36]([NH:38][C:39]([CH:41]5[CH2:42][CH2:43]5)=[O:40])[N:37]=4)[N:34]=3)=[CH:26][CH:25]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccccc1)Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1
Yield: 46.6 %

Procedure:
Using (2E)-3-phenylacrylic acid (135 mg, 0.91 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (80 μL, 0.91 mmol), N-[6-(4-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.65 mmol) and N,N-dimethylacetamide (4.0 mL), and in the same manner as in Example 255, the title compound (133 mg, 47%) was obtained as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].C([Li])CCC.CN(C)[CH:32]=[O:33]>O1CCCC1>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([CH:32]=[O:33])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(C=O)c1C(F)(F)F
Temperature: 60 °C

Procedure:
To a mechanically stirred solution of 10 g of 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoic acid in 400 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere was added 1.0 g of 95% sodium hydride. After the foaming subsided, the reaction was stirred and heated to 60° C. for one hour to ensure complete anion formation of the acid. The reaction was cooled to -110° C. with vigorous stirring and a 10.8 mL of 2.5M n-butyl lithium in hexanes was added maintaining the temperature below -100° C. As soon as the addition of n-butyl lithium was completed, 10 mL of dimethyl formamide was added and the solution was allowed to warm to -20° C. The reaction was then quenched with 3N HCl, and most of the volatiles were removed from the reaction mixture. The precipitate was filtered and recrystalized from carbon tetrachloride to give-3.0 g of 2-chloro-4-fluoro-5-[4-formyl-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzoic acid: mp 163° C.; 1HNMR (CDCl3) ppm: 9.82 (s, 1H), 7.89 (d, 1H, J=7.6), 7.07 (d, 1H, J=9.2), 3.39 (s, 3H). 19FNMR (CDCl3) ppm: -57.78, -107.41.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].[O:64]([CH2:72][C:73]1[CH:74]=[C:75]([CH:84]=[CH:85][CH:86]=1)[CH2:76]N=C([O-])C(Cl)(Cl)Cl)[Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:76][C:75]3[CH:84]=[CH:85][CH:86]=[C:73]([CH2:72][O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH:74]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN=C([O-])C(Cl)(Cl)Cl)c1
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCc4cccc(CO[Si](C)(C)C(C)(C)C)c4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4 -azatricyclo [22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (230 mg in 3 ml 33% methylene chloride in cyclohexane) was added m-(tert-butyldimethylsiloxymethyl)-benzyltrichloroacetimidate (198 μl neat) and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (4.5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 1 hour the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×8 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:2)+1% methanol) gave the title compound (165 mg)
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:6]=1[C:15](=[O:18])[CH2:16][CH3:17].Cl>CO>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)c1c(OCOC)cccc1OCOC
Agent: Cl
Solvent: CO
Product: CCC(=O)c1c(O)cccc1O
Yield: 99.9 %

Procedure:
1-(2,6-bis{[(methyloxy)methyl]oxy}phenyl)-1-propanone (Intermediate 27, 1.7 g) was dissolved in methanol (50.0 ml) and an aqueous solution of HCl (26.7 ml, 53.5 mmol of a 2M aqueous solution) was added. The reaction mixture was refluxed for 2 hours. After quenching with water, the reaction mixture was extracted with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated to afford the title compound (1.11 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[N:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[N:33]=[CH:32][C:31]([CH2:34][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:30][CH:29]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1ccc(Sc2ccc(C=O)cn2)cc1
Product: Cc1ccc(Sc2ccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cn2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 6-(4-methylphenyl)sulfanylpyridine-3-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[6-(4-methylphenyl)sulfanylpyridin-3-yl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([Br:26])=[CH:19][C:15]=1[C:16](O)=[O:17].Cl.[CH3:28][O:29][NH:30][CH3:31].O>C(Cl)Cl>[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([Br:26])=[CH:19][C:15]=1[C:16]([N:30]([O:29][CH3:28])[CH3:31])=[O:17]
Reactant: Nc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
1,1′-Carbonyldiimidazole (41 g) was added portionwise at room temperature to a mixture of 2-amino-5-bromo-3-nitro-benzoic acid (55 g) in DCM (700 ml). The mixture was stirred at room temperature for 1 hour. N-methoxy-methanamine hydrochloride (24.6 g) was added. The mixture was stirred at room temperature overnight and hydrolized with water. The precipitate was filtered off and the filtrate was decanted. The organic layer was dried, filtered and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/ethyl acetate 98/2). The pure fractions were collected and the solvent was evaporated. The precipitate was taken up in HCl 3N (250 ml). The mixture was stirred at room temperature for 4 hours. The precipitate was filtered off, washed with water and dried, yielding 23 g of 2-amino-5-bromo-N-methoxy-N-methyl-3-nitrobenzamide (interm. 55, mp. 129° C.)
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:13]([C:14](OCC)=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:22])[F:21])=[CH:9][N:10]=2)[N:5]=1)[CH3:2].C[Al](C)C.[F:28][C:29]1[CH:30]=[C:31]([CH2:35][NH2:36])[CH:32]=[CH:33][CH:34]=1>C1(C)C=CC=CC=1.O>[CH2:1]([S:3][C:4]1[C:13]([C:14]([NH:36][CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=2)=[O:15])=[C:12]([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:20]([F:23])([F:21])[F:22])=[CH:9][N:10]=2)[N:5]=1)[CH3:2]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)cnc2c1C
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCSc1nc2cc(C(F)(F)F)cnc2c(C)c1C(=O)NCc1cccc(F)c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
To a solution of ethyl 2-(ethylthio)-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.20 g, 0.58 mmol, 1 eq.) in toluene (6 ml) were added Me3Al(2M solution in toluene, 1.16 ml, 2.32 mmol, 4 eq.) and (3-fluorophenyl)methanamine (0.27 ml, 2.32 mmol, 4 eq.) at RT. The reaction mixture was stirred at 110° C. for 16 h. Afterwards the mixture was diluted with water (50 ml) and was extracted with EtOAc (3×40 ml). The combined organic layers were washed with a 0.5 M aq. HCl (60 ml), brine (60 ml), dried over anhydrous Na2SO4 and evaporated to provide the crude product, which was purified by CC (EtOAc/hexane 1:4) to yield 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-[1,5]naphthyridine-3-carboxylic acid amide (example 1) (0.14 g, 0.33 mmol, 57%). MS m/z [M+H]+ 424.1.
Reaction SMILES: S([O-])(O[CH3:5])(=O)=O.[S:7]([NH:17][C:18]1[C:19]([O:30][CH3:31])=[C:20]([N+:27]([O-:29])=[O:28])[C:21]([O:25][CH3:26])=[C:22]([Cl:24])[CH:23]=1)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[Na+]>>[S:7]([N:17]([C:18]1[C:19]([O:30][CH3:31])=[C:20]([N+:27]([O-:29])=[O:28])[C:21]([O:25][CH3:26])=[C:22]([Cl:24])[CH:23]=1)[CH3:5])([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:8])=[O:9]
Reactant: COc1c(Cl)cc(NS(=O)(=O)c2ccc(C)cc2)c(OC)c1[N+](=O)[O-]
Reactant: COS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: COc1c(Cl)cc(N(C)S(=O)(=O)c2ccc(C)cc2)c(OC)c1[N+](=O)[O-]
Reaction time: 0.25 h

Procedure:
0.022 mole (2.1 ml) of methyl sulphate was added at 30°-35° C. to a solution of 0.02 mole (7.7 g) of 5-(N-tosylamino)-2,4-dimethoxy-3-nitrochlorobenzene prepared in the previous step in 25 ml of a normal solution of sodium hydroxide. Stirring was continued for 15 minutes after completion of the addition. The expected product precipitated upon dilution of the reaction mixture with iced water. After thorough draining and washing with water, the product obtained was recrystallized from alcohol.