Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C.CC(N(C)C)=O>O1CCOCC1>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ncccn3)CC2)C1
Yield: 51 %

Procedure:
A stirred mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (0.2 mmol, 1 eq.), 2-chloropyrimidine (0.4 mmol, 2 eq.), DIPEA (2 eq.), DMA (2 eq.) in 1,4-dioxane (0.5 ml) was subjected to microwave radiation in a 10 ml pressure tube at 120° C. for 30 min. After concentration, the crude product was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) in order to obtain the desired product. Yield: 51%
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:13]=[CH:12]2)[S:8][C:7]=1[C:20]([O:22]C)=O.[NH3:28]>CO>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:10]=[C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:13]=[CH:12]2)[S:8][C:7]=1[C:20]([NH2:28])=[O:22]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 50 mg of methyl 3-[(2-fluorobenzyl)oxy]-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 15 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is recrystallized from 5 ml ethanol to yield the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CCCC[N+](CCCC)(CCCC)CCCC.[N-:51]=[N+:52]=[N-:53].[F:54][C:55]1[N:60]=[CH:59][C:58]([CH:61](O)[CH3:62])=[CH:57][CH:56]=1>C(Cl)Cl>[N:51]([CH:61]([C:58]1[CH:57]=[CH:56][C:55]([F:54])=[N:60][CH:59]=1)[CH3:62])=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(O)c1ccc(F)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a 1-L flask kept cold in an ice bath, add triphenylphosphine (27.9 g, 106.3 mmol), 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (24.12 g, 106.3 mmol). Add DCM slowly with stirring (150 mL). To the dark solution add tetra-N-butylammonium azide (30.23 g, 106.3 mmol) slowly, followed by 1-(6-fluoro-pyridin-3-yl)-ethanol (10 g, 70.85 mmol) dissolved in DCM (10 mL). Remove the flask from the ice bath and stir at RT for 1 h. Remove the solvent on a rotovap and purify by normal phase chromatography 5% to 20% ethyl acetate in hexanes to obtain the title compound as a colorless oil (7.75 g). GCMS m/z 166 [M]+.
Reaction SMILES: Cl.C(N[C:6](=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[C:7]([OH:9])=[O:8])(=O)C.[OH2:19].C1(C)C=CC=CC=1>CN1CCCC1=O>[Cl:18][C:13]1[CH:12]=[C:11]([CH2:10][C:6](=[O:19])[C:7]([OH:9])=[O:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(=O)NC(=Cc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: O=C(O)C(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 125 °C

Procedure:
140 mL 4 M HCl were added to a suspension of 21.0 g (76.6 mmol) 2-acetylamino-3-(3,4-dichloro-phenyl)-acrylic acid in 100 mL N-methyl-2-pyrrolidinone and the reaction mixture was then heated for 4 h at an oil bath temperature of 125° C. The cooled reaction solution was poured onto a cooled mixture of 350 mL water and 120 mL toluene. The phases were separated, the aqueous phase was again extracted with toluene, the combined organic phases were extracted with water, filtered through Na2SO4 and evaporated down i. vac. The residue was taken up in 1 M NaOH and washed twice with diethyl ether. The aqueous phase was acidified with 2 M HCl and extracted three times with EtOAc. The combined organic phases were filtered through Na2SO4 and evaporated down i. vac. The residue was combined with diethyl ether, suction filtered and dried in the vacuum drying cupboard.
Reaction SMILES: C(O[CH:4]([O:36]CC)[CH2:5][CH:6]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:7]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:11][CH:10]=1)[OH:8])C.S(=O)(=O)(O)O.O.[OH-].[Na+]>O1CCCC1>[OH:36][CH:4]1[O:8][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[CH:6]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5]1
Reactant: CCOC(CC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCN2CCOCC2)cc1)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1CC(c2ccccc2)C(c2ccccc2)(c2ccc(OCCN3CCOCC3)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The evaporation residue obtained in step (a) is dissolved in a mixture containing 19.5 g of concentrated sulfuric acid, 150 ml of water and 400 ml of tetrahydrofuran. The mixture is stirred for 3 h at room temperature. The solution is neutralized with 2 M sodium hydroxide solution and the solvent is evaporated. The product is extracted in toluene containing ethyl acetate. The solution is dried over sodium sulfate. The solvent is evaporated, and the residue is recrystallized from toluene. The yield is 12.0 g (27% from desoxybenzoin) of a product having m.p. 150°-3° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]2[N:11]([CH:12]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH2:13].[CH3:23]O>>[CH2:1]([O:2][CH2:3][C:4]1[C:5]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[C:6]2[N:11]([CH:12]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH2:13])[CH3:23]
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Reactant: CO
Product: CCOCc1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1

Procedure:
The method used in the preparation of Intermediate U was used to prepare the title compounds by substituting ethanol for methanol. MS [M+H]+=284.1; LCMS RT=0.35 min.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].O>C1COCC1>[CH3:8][N:9]([CH3:14])[S:10]([N:3]1[CH:7]=[CH:6][CH:5]=[N:4]1)(=[O:12])=[O:11]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of sodium hydride (5.2 g, 130 mmol, 60% in mineral oil) in anhydrous THF (50 mL) was added a solution of 1H-pyrazole (5.92 g, 87 mmol) in anhydrous THF (100 mL) at 0° C. The mixture was stirred for 30 minutes at room temperature. Dimethylsulfamoyl chloride (13.9 mL, 130 mmol) was added at 0° C., and then the mixture was stirred for 1.5 hours at room temperature. Water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the oil was passed through a short silica gel column using 20% hexane/ethyl acetate as a solvent. N,N-dimethyl-1H-pyrazole-1-sulfonamide was obtained as a yellow oil and used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1(O)[CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C[O:10][C:11]([CH3:13])=[CH2:12].OP(O)(O)=O.N#N>CC(OC)(C)C.C(N(CC)CC)C>[C:3]1(=[CH:1][CH2:2][CH2:12][C:11](=[O:10])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C=C(C)OC
Reactant: C=CC1(O)CCCC1
Agent: N#N
Agent: O=P(O)(O)O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)CCC=C1CCCC1
Temperature: 125 °C
Reaction time: 14 h
Yield: 68.8 %

Procedure:
A 600 ml autoclave containing a mixture of 1-ethenyl-cyclopentanol (172.0 g; 1.54 mol), isopropenyl methyl ether (218.8 g; 3.04 mol), triethylamine (1.65 ml) and 85% H3PO4 (0.72 ml) was pressurized with N2 at 2 bar and heated up to 125° C. An increase of the pressure to 7 bar was observed. After 14 hours stirring, the autoclave was cooled down to room temperature and depressurized. MTBE (1.5 l) was added to the mixture, washed with H2O (4×25 ml) until neutral pH, dried (MgSO4) and concentrated. Distillation (61° C./0.1 torr) yielded 161.3 g (69% yield) of 5-cyclopentylidenepentan-2-one.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#N)=[CH:13][CH:12]=1)[CH2:6]2.C(O)=[O:20]>[Ni]>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:20])=[CH:13][CH:12]=1)[CH2:6]2
Reactant: CN1C2CCC1CC(Oc1ccc(C#N)cc1)C2
Reactant: O=CO
Agent: [Ni]
Product: CN1C2CCC1CC(Oc1ccc(C=O)cc1)C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The title compound was synthesized by referring to Chem. Pharm. Bull., 1991, 39, 1440. To a solution of 4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)benzonitrile (300 mg) in formic acid (5 ml) was added Raney nickel (50% suspension in water) (1 ml), and the solution was stirred for 2 hours at 100° C. After filtration through celite pad and several wash with tetrahydrofuran and methanol, the solvent was evaporated in vacuo, and the resulting residue was neutralized by adding a saturated aqueous solution of sodium bicarbonate. After extraction with chloroform and washing with brine, the solution was dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo to provide the title compound (266 mg).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1.P(Br)(Br)([Br:24])=O.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>O>[Br:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)c1ccc(-n2nc(O)c3ccccc3c2=O)cc1
Reactant: O=P(Br)(Br)Br
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Product: CC(C)c1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
4-Hydroxy-2-(4-isopropylphenyl)-2H-phthalazin-1-one (0.10 g, 0.36 mmol), phosphorus oxybromide (0.41 g, 1.4 mmol) and 2,6-di-tert-butyl-4-methylphenol (0.02 g, 0.09 mmol) were stirred at 150° C. for 30 min. H2O (100 ml) was added after cooling to room temperature. Extraction with dichloromethane, drying of the combined organic phases over Na2SO4 and evaporation of the solvent yielded the desired compound (0.05 g, 41%) which was used without any further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][N:28]4[CH:36]=[CH:37][CH:38]=[C:27]4[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[N:13]1.C(NC(C)C)(C)C>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH2:29][N:28]4[CH:36]=[CH:37][CH:38]=[C:27]4[CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[N:13]1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: O=C(c1ccc(-c2ccn(C(=O)c3ccc(F)cc3Cl)n2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Portionwise, 2-chloro-4-fluorobenzoyl chloride (0.82 g) was added to a solution of [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g) and diisopropylamine (0.55g) in dichloromethane (25 ml) which was cooled in an ice bath. The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was washed with water and saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The dichloromethane solution was passed through a short column of hydrous sodium magnesium silicate, eluting several additional volumes of dichloromethane. The eluent was evaporated to dryness to yield 1.06 g of the product as a solid, m.p. 150-157° C.; MS, m/z: 510 (M)+.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)=[O:22])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(Cl)[Cl:35]>>[ClH:35].[NH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:2](=[O:1])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)(C)OC(=O)NCCNC(=O)CCCCCn1c2ccccc2c(=O)c2ccccc21
Reactant: ClCCl
Product: Cl
Product: NCCNC(=O)CCCCCn1c2ccccc2c(=O)c2ccccc21

Procedure:
To 0.30 g of tert-butyl 2-{[6-(9-oxoacridin-10(9H)-yl)hexanoyl]amino}ethylcarbamate was added dicholoromethane (DCM; 30 ml). HCl (g) was bubbled through the solution for 10 minutes. After this time the mixture was filtered and washed with DCM (3×20 ml) to give the desired product (0.15 g; Formula XIX). Mass spectrum: 352 (M+H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]/[CH2:7][C:8]1[C:13]([O:14]C(=O)C)=[C:12]([CH3:18])[C:11]([CH3:19])=[C:10]([O:20]C(=O)C)[C:9]=1[CH3:24])/[CH2:3][C:4]#N.C=C(CCC1C(OC(=O)C)=C(C)C(C)=C(OC(=O)C)C=1C)CC#N.[OH-:49].[K+].Cl.[OH2:52]>C(O)CO>[OH:20][C:10]1[C:11]([CH3:19])=[C:12]([CH3:18])[C:13]2[O:14][C:2]([CH2:3][C:4]([OH:52])=[O:49])([CH3:1])[CH2:6][CH2:7][C:8]=2[C:9]=1[CH3:24]
Reactant: CC(=O)Oc1c(C)c(C)c(OC(C)=O)c(C/C=C(/C)CC#N)c1C
Reactant: O
Reactant: [OH-]
Agent: C=C(CC#N)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Agent: Cl
Agent: [K+]
Solvent: OCCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 623 mg (1.89 mmoles) of the mixture of E-and Z-3-methyl-5-(2,4,5-trimethyl-3,6-diacetyloxyphenyl)-3-pentenenitrile and 3-methylene-5-(2,4,5-trimethyl-3,6-diacetyloxy-phenyl)pentanenitrile, 498 mg (7.70 mmoles) of 85% KOH, 5 ml of ethylene glycol and 0.5 ml of water was stirred and refluxed for 36 hr. The reaction mixture was cooled to room temperature, then poured into water. The pH of the solution was adjusted to 8 with 1 N aqueous HCl and the resulting mixture was extracted with two portions of ether (the extracts were discarded). The aqueous phase was acidified with 3 N aqueous HCl and worked-up with ether in the usual manner giving 421 mg (84%) of rac.-(6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)acetic acid as a tan solid, mp 168°-170°.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:35][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: ClCCCN1CCCCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CCCN2CCCCC2)c2ccc(C#CCO)cc2c1=O
Temperature: 90 °C
Reaction time: 38 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.367 g) is dissolved in DMF (10 mL), and K2CO3 (0.55 g) and N-(3chloropropyl)piperidine hydrochloride (0.408 g) are added. The reaction mixture is heated to 90° C. for 10 h, and then allowed to stir at room temperature for 38 h. Water is added and a precipitate formed. The precipitate is filtered and allowed to dry at room temperature and then under reduced pressure to give 0.187 g of a solid. The solid is dissolved in CHCl3 and filtered to remove 0.045 g of a precipitate. The filtrate is concentrated in vacuo and crystallized from ethyl acetate to give 0.065 g of the title compound as a solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:33][O:32][C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([CH2:35][CH2:34][C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH2:41])=[O:40])[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Reactant: C#Cc1cccc(C(N)=O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I34) 0.098 g, 0.20 mmol), 3-ethynylbenzamide (I31) (0.038 g, 0.26 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol), triphenylphosphine (0.010 g, 0.04 mmol) and copper(I) iodide (0.009 g, 0.05 mmol) in DMF (2 mL), that had been degassed with nitrogen for 10 minutes, was added triethylamine (0.090 mL, 0.65 mmol). The mixture was degassed with nitrogen then heated to 120° C. for 25 minutes under microwave irradiation. On cooling to room temperature the resulting mixture was left overnight, then an additional portion of 3-ethynylbenzamide (I26) (0.047 g, 0.32 mmol) was added. After degassing with nitrogen the reaction was heated at 120° C. for 25 minutes under microwave irradiation. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (20-70% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 61%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.04 (dd, J=1.4, 1.4 Hz, 1H), 8.02 (s, 1H), 7.93 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 7.80 (m, 1H), 7.53 (m, 1H), 6.88 (dd, J=8.3, 1.6 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.27 (m, 2H), 3.91 (s, 3H), 2.81 (m, J=12.2 Hz, 2H), 2.64 (tt, J=12.2, 3.4 Hz, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.59 min; m/z 496.1 [(M-Boc)+H]+, 540.0 [(M-t-Bu)+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH2:6].C[Si](CCOCCl)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[N:30][N:29]=1.CN1C=CN=C1>CC#N>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:28]1[C:37]2[C:32](=[CH:33][C:34]([S:38]([NH:6][C:2]3[S:1][CH:5]=[CH:4][N:3]=3)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH:31]=[N:30][N:29]=1
Reactant: Nc1nccs1
Reactant: COc1cc(C(F)(F)F)ccc1-c1nncc2cc(S(=O)(=O)Cl)ccc12
Agent: C[Si](C)(C)CCOCCl
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)(F)F)ccc1-c1nncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 1 h

Procedure:
A solution of thiazol-2-amine (0.027 g, 0.273 mmol) in 3 mL of MeCN was treated with SEM-Cl (0.048 ml, 0.273 mmol), and the reaction mixture was allowed to stir for one hour. LC/MS showed mostly product, so 1-(2-methoxy-4-(trifluoromethyl)phenyl)phthalazine-6-sulfonyl chloride (Intermediate BBBB; 0.100 g, 0.248 mmol) was added as a solution in 3 mL of MeCN, followed by 1-methylimidazole (0.049 ml, 0.497 mmol). After stirring at room temperature for an additional hour, LC/MS showed mostly desired product. The reaction mixture was concentrated then dissolved in 4N HCl in dioxanes (1.862 ml, 7.45 mmol), and the reaction mixture was heated to 110° C. for 3 hours. The reaction mixture was concentrated and was purified by reverse phase column chromatography [C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] to yield 1-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)phthalazine-6-sulfonamide. 1H NMR (acetonitrile-d3) δ ppm: 9.70 (s, 1H), 8.63 (s, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.45-7.53 (m, 2H), 7.02 (d, J=4.7 Hz, 1H), 6.65 (d, J=4.7 Hz, 1H), 3.75 (s, 3H). m/z (ESI) 467.0 (M+H)+
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([C:16]2C=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8](C(O)=O)=[CH:9][CH:10]=[CH:11][CH:12]=1>ClCCl.CN(C)C=O>[C:16]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:1]([C:2]([Cl:4])=[O:3])=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1-c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1-c1ccccc1

Procedure:
1.54 ml (0.018 mol) of oxalyl chloride are added dropwise to a suspension of 3 g (0.015 mol)) of biphenyl-2-carboxylic acid in 100 ml of dichloromethane and 0.3 ml dimethylformamide at 0° C. After the reaction has ended the reaction mixture is concentrated by distillation and the biphenyl-2-carboxylic acid chloride is further reacted as a crude product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C[Al](C)C.C[O:13][C:14]([C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]=[C:18]([CH3:30])[N:17]=1)=O>O1CCOCC1.CCCCCC>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[N:19]=[C:18]([CH3:30])[N:17]=2)=[O:13])[S:3][CH:4]=1
Reactant: COC(=O)c1cc(-c2cc(F)cc(F)c2)nc(C)n1
Reactant: Cc1csc(N)n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1csc(NC(=O)c2cc(-c3cc(F)cc(F)c3)nc(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a solution of 156 mg (1.37 mmol, 1.8 equiv.) of 2-Amino-4-methylthiazole in 4 ml of dry dioxane were added 0.68 μl (1.37 mmol, 1.8 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 1 h at room temperature. Then 200.0 mg (0.76 mmol) of 6-(3,5-Difluoro-phenyl)-2-methyl-pyrimidine-4-carboxylic acid methyl ester were added and the reaction was heated to 90° C. for 4 h. The reaction was quenched by cautious addition of 0.2 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue was purified by flash chromatography (heptane/ethyl acetate 4:1) and recristallised from diisopropyl ether to yield the title compound (152.0 mg, 58%) as a white solid, MS (ISP): m/e=347.1 (M+H)+.