Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]2=[O:15].[CH3:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[NH:4]1[CH:3]=[CH:2][N:1]=[C:10]1[CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[NH:6][C:5]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([CH3:16])[CH2:18][CH2:19]1)=[O:15]
Reactant: O=C1Nc2ccccc2Cc2nccn21
Reactant: CN1CCCNCC1
Solvent: ClCCl
Product: CN1CCCN(C(=O)Nc2ccccc2Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 0.76 g of 11H-imidazo[1,2-c][1,3]benzodiazepin-5-(6H)-one in 9 ml of methylene chloride was added at once 0.41 g of N-methylhomopiperazine and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. Recrystallization of the residue from methylene chloride-ether gave 1-[2-(2-imidazolylmethyl)phenylcarbamoyl]-4-methylhomopiperazine, the compound of formula VI wherein R1, R2, R4 -R7 are hydrogen, CnH2n is (CH2)3, R3 is methyl and Z is oxygen, melting at 139°-143°.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:42]([CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[O:43])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (70%→90% ethyl acetate in hexanes) affording the desired product (70) as a solid. ESMS: MH+ 590.6
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]([NH2:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[C:13]([NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[F:1])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)N
Reactant: Cc1cccc(C(=O)O)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(C)(C)C)c1F
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a stirred solution of 2-fluoro-3-methylbenzoic acid (8.76 mmol, 1.35 g), 2-methylpropan-2-amine (9.43 mmol, 1 mL, 0.690 g) and triethylamine (28.7 mmol, 4 mL, 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (13.50 mmol, 8 mL, 8.59 g, 50% solution in ethyl acetate). The reaction was stirred for 2 hours and diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under reduced pressure to yield the title compound (1 g).
Reaction SMILES: CN(C)/[CH:3]=[C:4](\[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)/[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:21]([CH2:23][C:24]([NH2:26])=[O:25])#[N:22].CO.[H-].[Na+]>CN(C=O)C>[OH:25][C:24]1[N:26]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][C:23]=1[C:21]#[N:22]
Reactant: N#CCC(N)=O
Reactant: Cc1ccc(/C(=C\N(C)C)C(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-c2cc(C#N)c(O)nc2-c2ccccc2)cc1
Temperature: 95 °C

Procedure:
A solution of (E)-3-(dimethylamino)-1-phenyl-2-p-tolylprop-2-en-1-one (Compound 113, 500 mg, 1.9 mmol), cyanoacetamide (175 mg, 2.1 mmol) and MeOH (0.2 ml, 2.2 mmol) in DMF (4 ml) was cannulated into a suspension of NaH (119 mg, 4.7 mmol, 95% in mineral oil) in DMF (2 ml) at room temperature. After the addition was completed, the reaction was heated to 95° C. for 2 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, concentrated in vacuo. The solid residue was triturated with diethyl ether, filtered and dried under high vacuum to yield the title compound as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:18])=[O:17])O1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]3[CH:39]=[CH:38][NH:37][C:34]3=[N:35][CH:36]=2)=[C:27]([F:40])[CH:26]=1>>[F:40][C:27]1[CH:26]=[C:25]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH:20]([CH3:21])[CH3:22])(=[O:17])=[O:18])[CH:30]=[CH:29][C:28]=1[C:31]1[N:32]=[C:33]2[CH:39]=[CH:38][NH:37][C:34]2=[N:35][CH:36]=1
Reactant: Fc1cc(Br)ccc1-c1cnc2[nH]ccc2n1
Reactant: CC(C)CS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CC(C)CS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc3[nH]ccc3n2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 490 using N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isobutylsulfonamide and 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): mass calcd. C22H21FN4O2S, 424.14; m/z found, 425.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.78 (d, J=2.6, 1H), 8.20-8.11 (m, 1H), 7.73-7.65 (m, 2H), 7.46-7.37 (m, 1H), 7.34-7.29 (m, 2H), 7.26-7.19 (m, 2H), 6.87-6.79 (m, 1H), 6.59 (s, 1H), 2.97 (d, J=6.6, 2H), 2.31-2.13 (m, 1H), 1.05 (d, J=6.7, 6H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.Br[C:14]1[N:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>>[Cl:20][C:17]1[CH:16]=[N:15][C:14]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[N:19][CH:18]=1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Reactant: Clc1cnc(Br)nc1
Product: CN(c1ncc(Cl)cn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 120 °C

Procedure:
In analogy to example 1.7, trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol and 1.5 equivalent of 2-Bromo-5-chloro-pyrimidine [synthesized from 5-chloro-2-hydroxy-pyrimidine in analogy to Brown, Desmond J.; Arantz, B. W., Pyrimidine reactions. XXII. Relative reactivities of corresponding chloro-, bromo-, and iodopyrimidines in aminolysis. J. Chem. Soc. C (1971), Issue 10, 1889–91] were heated for 0.5 h at 80° C., 1 h at 120° C., then 0.5 equivalent of 2-Bromo-5-chloro-pyrimidine were added and heated for 1 h at 120° C. to give after work up trans-3-{4-[(5-Chloro-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, mp: 148–150° C., dec.; MS: 280 (MH+, 1Cl).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.CSC.[N:11]1([CH:16]([C:18]([C:20]([CH3:30])([CH3:29])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=O)[CH3:17])[CH:15]=[N:14][CH:13]=[N:12]1.C[O-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]([C:18]2([CH:16]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH3:17])[CH2:7][O:6]2)([CH3:29])[CH3:30])=[CH:23][CH:24]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(n1cncn1)C1(C(C)(C)Cc2ccc(Cl)cc2)CO1
Reaction time: 20 h
Yield: 98.1 %

Procedure:
A solution of 9.8 g (0.77 mole) of dimethyl sulphate and 5.3 g (0.085 mole) of dimethyl sulphide in 50 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 13 g (0.044 mole) of 4-chlorophenyl-tert.butyl 1-(1,2,4-triazol-1-yl)-ethyl ketone in 20 ml of acetonitrile is then added dropwise at room temperature. At the same temperature, 4.8 g (0.088 mole) of sodium methylate are introduced and the mixture is subsequently stirred for 20 hours and then concentrated in vacuo. The residue is stirred overnight with a mixture of 35 ml of ethyl acetate and 25 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 13.2 g (98.2% of theory) of 2-(4-chlorophenyl-tert.-butyl)-2-[1-(1,2,4-triazol-1-yl)-ethyl]oxirane of refractive index nD20 1.5431 are obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=1)[OH:10].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:5]([O:4][C:2]([NH:7][CH2:8][CH:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]2([CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:12]=1)[OH:10])=[O:3])[CH3:6]
Reactant: NCC(O)C1=CC2(CCCC2)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NCC(O)C1=CC2(CCCC2)c2ccccc21
Reaction time: 2 h

Procedure:
Ethyl chloroformate (2.06 g) is added dropwise at about 7° C. to a stirred mixture of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol (3.35 g) in chloroform (50 ml) and sodium hydroxide (0.9 g) in water (20 ml). After 2 hours, the chloroform phase is separated and the aqueous phase is extracted twice with chloroform. The combined chloroform solutions are dried and concentrated under reduced pressure. The crude 2-ethoxycarbonylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol thus obtained is dissolved in tetrahydrofuran (50 ml) and added dropwise to lithium aluminium hydride (1.8 g) in tetrahydrofuran (150 ml). After refluxing for 3 hours, the mixture is cooled and decomposed with a slight excess of saturated sodium sulphate solution. The solid precipitate is filtered off and washed with tetrahydrofuran. The combined filtrate and washings are dried and the solvent is removed, finally under reduced pressure. The residual oil crystallizes on scratching. Crystallization from diisopropyl ether gives the title compound; m.p. 134° C. 2-Ethylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is similarly obtained when using acetic anhydride instead of ethyl chloroformate and reduction of the crude N-acetyl derivative. The free base is obtained as an oil, which is converted to the hydrochloride by treatment with hydrogen chloride in diethyl ether, m.p. 227° C. after crystallization from isopropyl alcohol. An identical product is obtained by reduction of crude 2-acetamido-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol acetate obtained by the treatment of 2-amino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol with acetylchloride in diethyl ether containing an excess of triethylamine, removal of the precipitated triethylamine hydrochloride by filtration and evaporation of the filtrate.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH3:5])[CH3:3].[OH:6][C:7]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[OH:6][C:7]1[CH:20]=[C:19]([OH:21])[C:18]([C:2]([CH3:3])([CH3:1])[CH2:4][CH3:5])=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]
Reactant: CC=C(C)C
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Reaction time: 6 h
Yield: 89.8 %

Procedure:
42 g (0.6 mol) of 2-methyl-2-butene are added dropwise to a solution of 45 g (0.21 mol) of 2,4-dihydroxybenzophenone and 6.1 g (63 mmol) of methanesulfonic acid in 90 ml of toluene and the mixture is held at 75° C. with stirring for 6 h. The reaction mixture is cooled, then treated with 100 ml of NaHCO3 and extracted with ethyl acetate. The resulting solution is washed with water and then with saturated sodium chloride solution. The residue which remains after drying over MgSO4, filtering and concentrating by evaporation is recrystallized from CH2Cl2 /hexane. 53.6 g (89.9%) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone are obtained as beige crystals having a melting point of 100°-104° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:15])[C:3]=1[N+:16]([O-:18])=[O:17].[NH2:19][C:20]1[C:21]([S:28][CH3:29])=[N:22][CH:23]=[N:24][C:25]=1[S:26][CH3:27].CC([O-])(C)C.[K+]>CS(C)=O>[Cl:15][C:4]1[C:3]([N+:16]([O-:18])=[O:17])=[C:2]([N:24]2[C:25]([S:26][CH3:27])=[C:20]([NH2:19])[C:21]([S:28][CH3:29])=[N:22][CH2:23]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CSc1ncnc(SC)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CSC1=NCN(c2c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c2[N+](=O)[O-])C(SC)=C1N
Temperature: 20 °C
Reaction time: 15 h
Yield: 9737.8 %

Procedure:
7.32 g (0.24 mmole) of 1,3-dichloro-2,6-dinitro-4-trifluoromethylbenzene are dissolved in 30 ml of dimethylsulfoxide and then a solution of 3.75 g (20 mmoles) of 5-amino-4,6-dimethylthiopyrimidine in 20 ml of dimethylsulfoxide and a solution of 2.69 g of potassium tert-butylate in 20 ml of dimethylsulfoxide are added simultaneously dropwise at 15° C. with cooling. The reaction solution is stirred for 15 hours at 20° C. and then poured into ice-water and, after neutralisation with acetic acid, extracted three times with chloroform. The extracts are washed with water, dried over sodium sulfate, and the chloroform is removed, affording 10.7 g of a yellow oil. The crude product is purified by chromatography through a solumn of silica gel, affording 2.04 g of starting 5-amino-4,6-di(methylmercapto)pyrimidine and 2.8 g of a yellow product which is recrystallised from 1 ml of toluene and 5 ml of cyclohexane to give 2.03 g of compound 1.2 of m.p. 146°-147° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=O)[NH:7][CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].S(Cl)(Cl)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:28]([C:34]([NH:36][NH2:37])=O)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)(=[O:25])=[O:24])=[CH:19][C:18]=1[C:38]([F:41])([F:40])[F:39]>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:26][C:27]2[C:28]([C:34]3[N:7]([CH:8]([CH3:10])[CH3:9])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:37][N:36]=3)=[N:29][CH:30]=[C:31]([Cl:33])[CH:32]=2)(=[O:24])=[O:25])=[CH:19][C:18]=1[C:38]([F:39])([F:41])[F:40]
Reactant: CCOC(=O)C(=O)NC(C)C
Reactant: NNC(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)n1C(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.2 %

Procedure:
To a vial containing ethyl(isopropylcarbamoyl)formate (160 mg, 1.0 mmol) was added thionyl chloride (1.0 mL, 13.8 mmol). The vial was capped with a teflon coated septa and heated to 80° C. for 5 h. After cooling to room temperature, the volatiles were removed in vacuo. A solution of 4-chloro-N-(5-chloro-2-(hydrazinecarbonyl)pyridine-3-yl)-3-(trifluoromethyl)benzenesulfonamide (342 mg, 0.80 mmol) in toluene (3 mL) was added. The mixture was stirred at 40° C. for 16 h. After cooling to room temperature, the toluene was removed in vacuo. Ethanol (9 mL) and triethylamine (1 mL) were added, and the solution heated to 90° C. for 4 h. After cooling to room temperature, the volatiles were removed in vacuo, and the resulting residue purified by flash chromatography on 4 g of silica gel (0→20% gradient of MeOH in DCM). The pure fractions were collected, and the solvent removed in vacuo to afford the title compound (14 mg, 3% yield). HPLC retention time=3.17 minutes. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=2.4, 1H), 8.19 (d, J=2.4, 1H), 8.04 (d, J=2.4, 1H), 7.89 (dd, J=2.0, 8.4, 1H), 7.53 (d, J=8.0, 1H), 5.66 (sept, J=7.0, 1H), 4.52 (q, J=7.4, 2H), 1.52 (d, J=7.0, 6H), 1.50 (t, J=7.4, 3H). MS (ES) [M+H]+ expected 552.0, found 552.0.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[CH:18]=[N:19][C:20]([C:30]#[C:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N)CN>[Pd].CO>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([CH3:38])[C:17]2[CH:18]=[N:19][C:20](/[CH:30]=[CH:31]\[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(C#Cc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: NCCN
Solvent: CO
Product: Cc1ccccc1-c1cc(/C=C\c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A mixture of 100 mg (0.198 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-phenylethynyl-4-o-tolyl-pyridin-3-yl)-isobutyramide (Example 72), 10 mg (0.17 mmol) ethylenediamine and 1 mg 10% palladium on carbon in 2 ml methanol was stirred at room temperature under an atmosphere of hydrogen gas for 8 h. The reaction mixture was filtered and concentrated. Column chromatography afforded 28 mg (24%) of the title compound as an orange viscous oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][N:52]([C:55](=[O:57])[CH3:56])[CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl.CCCCCCC>[C:55]([N:52]1[CH2:53][CH2:54][N:49]([CH2:48][CH2:47][O:24][C:21]2[CH:22]=[CH:23][C:18]([CH:15]3[CH2:16][CH2:17][N:12]([C:9]4[CH:10]=[CH:11][C:6]5[N:7]([C:3]([C:2]([F:1])([F:25])[F:26])=[N:4][N:5]=5)[N:8]=4)[CH2:13][CH2:14]3)=[CH:19][CH:20]=2)[CH2:50][CH2:51]1)(=[O:57])[CH3:56]
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CC(=O)N1CCN(CCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 23.5 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
Dichloromethane (225.0 mL) and 4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (50.0 g, 138 m mol) were charged to a suitable round bottom flask at 22-25° C. Triphenylphosphine (72.2 g, 275 m mol) and 1-[4-(2-hydroxy-ethyl)piperazin-1-yl]ethanone [CAS: 83502-55-0] (47.4 g, 275 m mol) were added successively to the reaction mass and stirred for 10 min at 22-25° C. Di-isopropyl azodicarboxylate (55.65 g, 275 m mol) in dichloromethane (75.0 mL) was added to the reaction mass slowly drop wise at 25-30° C. over a period of 60-90 min. The resulting reaction mass was stirred for 1.0 h at 25-30° C. to complete the reaction. n-Heptane (600.0 mL) was introduced to the reaction mass by drop wise addition over a period of 15-30 min at 22-25° C. and stirred for 30 min at the same temperature. Thus precipitated solid was filtered and washed with n-heptane (150.0 mL). The material was then suck dried for 30 min under reduced pressure. The crude material was purified by slurry washing in methanol (325.0 mL) at 22-25° C. The solid was then collected by filtration and washed with methanol (50.0 mL). The material was dried under reduced pressure with nitrogen gas bleed at 50° C. to afford the desired product 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (61.2 g, 84%) as a free flowing solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[CH:15]=[C:14]([CH3:16])[S:13][C:12]=1Br)=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:16][C:14]1[S:13][C:12]2[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[NH:8][C:9](=[O:10])[C:11]=2[CH:15]=1
Reactant: Cc1cc(C(=O)Nc2ccccc2O)c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
To a solution of N-(2-hydroxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (15 g) in dimethyl sulfoxide (100 ml) was added potassium carbonate (13 g), and the mixture was stirred at 140° C. for 1.5 hours. The reaction system was cooled to room temperature and the reaction mixture was poured into water (800 ml). After neutralization with hydrochloric acid, the mixture was extracted twice with chloroform and washed with water and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. To the residue was added chloroform and the crystals were collected by filtration to give 2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (3.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:8]=[C:9]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CC2CCCC2)c[nH]1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(CC2CCCC2)cn1Cc1ccc(F)cc1F
Reaction time: 18 h

Procedure:
A mixture of 4-cyclopentylmethyl-1H-pyrrole-2-carboxylic acid ethyl ester (A1-II) and cesium carbonate were stirred in dry DMF for 10 minutes at 40-50° C. To it 1-bromomethyl-2,4-difluorobenzene was added and the reaction was stirred for 18 hrs. at 50° C. Water was added to the reaction and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4-cyclopentylmethyl-1-(2,4-difluorobenzyl)-1H-pyrrole-2-carboxylic acid ethyl ester (A1-III).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:11])=[N:7][NH:8][C:9]=1[NH2:10])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:14]=[CH:15][CH:16]=O>C(O)C.C(O)(=O)C>[C:1]([C:5]1[C:6]([NH2:11])=[N:7][N:8]2[CH:16]=[CH:15][CH:14]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)n[nH]c1N
Reactant: CN(C)C=CC=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1c(N)nn2cccnc12
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture from Example 105A (2.61 g, 16.9 mmol), 3-dimethylaminoacrylaldehyde (2.0 mL, 20.0 mmol) and acetic acid (25 μL, 0.44 mmol) in ethanol (18 mL) was heated by microwave to 150° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (EtOAc, Rf=0.39) afforded 2.34 g (43%) of the title compound. MS (DCI) m/z 191 (M+H)+.