Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:10]=[C:9]([O:30][CH3:31])[N:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([NH:13][S:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)(=[O:15])=[O:16])[CH:10]=[C:9]([O:30][CH3:31])[N:8]=1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(Cl)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(Cl)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 15 using tert-butyl 4-[({2-[(3-chloro-2-fluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]piperazine-1-carboxylate (the product from step ii) (0.26 g), trifluoroacetic acid (0.5 mL) and DCM (10 mL). Purification was by reverse phase HPLC (Symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then triturated with MeOH followed by Et2O to give the title compound as a white solid. Yield: 40 mg
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[C:9](Br)[S:10][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18](B(O)O)[S:19][CH:20]=1>>[NH2:1][C:2]1[C:7]2[CH:8]=[C:9]([C:18]3[S:19][CH:20]=[C:16]([CH3:15])[CH:17]=3)[S:10][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Reactant: Cc1csc(B(O)O)c1
Product: Cc1csc(-c2cc3c(N)ncc(C(N)=O)c3s2)c1

Procedure:
19 was prepared from 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 and 4-methyl-2-thiopheneboronic acid according to the general procedure described in Example 2. 1H NMR (400 MHz, d6-DMSO) δ: 2.25 (s, 3H), 7.29 (s, 1H), 7.36 (s, 1H), 7.80 (br s, 1H), 8.14 (s, 1H), 8.40 (br s, 1H), 8.46 (s, 1H). MS (EI) m/z (M+H+) 290.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)[N:10]=1)C1C=CC=CC=1.C(NC1C=C(C)C=C(N2C=CN=N2)N=1)C1C=CC=CC=1.Cl.[H][H].[OH-].[Na+]>CO.[Pd]>[CH3:15][C:13]1[CH:12]=[C:11]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)[N:10]=[C:9]([NH2:8])[CH:14]=1
Reactant: [H][H]
Reactant: Cc1cc(NCc2ccccc2)nc(-n2nccn2)c1
Agent: [Pd]
Agent: Cc1cc(NCc2ccccc2)nc(-n2ccnn2)c1
Agent: Cl
Solvent: CO
Product: Cc1cc(N)nc(-n2nccn2)c1
Reaction time: 14 h

Procedure:
The 1:1 regioisomeric mixture of N-benzyl-4-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (316 mg, 1.19 mmol) and N-benzyl-4-methyl-6-(1H-1,2,3-triazol-1-yl)pyridin-2-amine (316 mg, 1.19 mmol) from the previous step was dissolved in methanol (10 mL). Hydrochloric acid (37% in water, 1.96 mL, 23.8 mmol) and palladium on carbon (127 mg, 0.119 mmol, 10 wt %) were added. The flask was fitted with a hydrogen balloon and evacuated and backfilled with hydrogen (3×). The reaction mixture was stirred under an atmosphere of hydrogen for 14 hours. The reaction mixture was filtered, diluted with sodium hydroxide (1.0 M in water, 30 mL, 30 mmol), and extracted with ethyl acetate (3×). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (25-50% ethyl acetate/hexanes, linear gradient) afforded 4-methyl-6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine. MS ESI calc'd. for C8H10N5 [M+H]+ 176. found 176. 1H NMR (500 MHz, CD3OD) δ 7.93 (s, 2H), 7.11 (s, 1H), 6.40 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[C@@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCC(O)CC1
Reactant: C[C@H]1CNC(=O)c2cc3cc(O)ccc3n21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@@H](C)CNC2=O)CC1
Yield: 52 %

Procedure:
The title compound was synthesized in analogy to example 1, from (S)-8-hydroxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow foam (52%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([OH:14])[CH:10]=[CH:11][C:12]#[CH:13]>C(NC(C)C)(C)C.[Cu]I.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>[OH:14][CH2:9]/[CH:10]=[CH:11]/[C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([C:13]#[C:12]/[CH:11]=[CH:10]/[CH2:9][OH:14])=[CH:4][CH:3]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CC=CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: OC/C=C/C#Cc1ccc(C#C/C=C/CO)cc1
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To a solution of 1,4-diiodobenzene (1.32 g, 4.0 mmol) in diisopropylamine (12 mL) under a nitrogen atmosphere were added copper(I) iodide (60 mg, 0.3 mmol) and tetrakis(triphenylphosphine)palladium (80 mg, 0.07 mmol). After the mixture stirred for 1 h, a solution of 2-penten-4-yn-1-ol (1.0 g, 12.0 mmol) in diisopropylamine (7 mL) was added. After stirring under a nitrogen at 60° C. for 8 h, the reaction mixture was filtered and the filtrate evaporated to dryness. The product was purified by flash chromatography using toluene/ethyl acetate (2:1) graduated to ethyl acetate as eluent to give 520 mg (55%) of (E)(E) 5-[4-(5-hydroxy-pent-3-en-1-ynyl)-phenyl]-pent-2-en-4-yn-1-ol.
Reaction SMILES: C(C1C=CC(C[S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=CC=1)C.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][S:8][C:9]2[CH:10]=[C:11]([O:19][CH2:20][O:21][CH3:22])[C:12](=[O:18])[N:13]([CH2:15][O:16][CH3:17])[CH:14]=2)=[N:28][CH:29]=1
Reactant: CCc1ccc(CSc2cc(OCOC)c(=O)n(COC)c2)cc1
Reactant: ClCc1ccc(Cl)cn1
Product: COCOc1cc(SCc2ccc(Cl)cn2)cn(COC)c1=O

Procedure:
Prepared as described for 5-[(4-ethylbenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 17) but using 2-chloromethyl-5-chloropyridine instead of 1-(chloromethyl)-4-ethylbenzene.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:12][C:13]([C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]3)=[N:19][N:18]2[CH:42]=1)=O)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:41])[C:30]5[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=5[C:37]([F:38])([F:40])[F:39])[CH2:25][CH2:24]4)=[N:19][N:18]3[CH:42]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Product: O=C(NCc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 38 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-fluorobenzylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 38% yield. 1H NMR (300 MHz, CDCl3) δ 8.19 (d, J=3.0 Hz, 1H), 7.76-7.72 (m, 1H), 7.69-7.6 (m, 2H), 7.35-7.3 (m, 2H), 7.27-7.19 (m, 1H), 7.09-6.94 (m, 3H), 6.89 (d, J=9.9 Hz, 1H), 4.59 (d, J=6.3 Hz, 2H), 4.05-3.94 (m, 1H), 3.91-3.8 (m, 1H), 3.69-3.54 (m, 2H), 3.52-3.43 (m, 2H), 3.38-3.29 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 166.0, 162.6, 162.1, 160.5, 154.8, 137.6, 135.5, 134.1, 134.0, 129.7, 129.6, 126.2, 118.6, 116.8, 116.6, 115.6, 115.3, 114.9, 114.6, 112.2, 46.2, 45.6, 42.5, 41.3. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH:30]([CH3:32])[CH3:31])=[CH:11][CH:10]=1)#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH:30]([C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:35][N:34]=[N:33][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1cccc2nc(C(C)C)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc2nc(C(C)C)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reaction time: 120 h
Yield: 51.4 %

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-isopropylbenzimidazole-7-carboxylate (2.12 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DMF (15 ml) was stirred for 5 days at 110°-120 C. To the reaction mixture was added water (150 ml), which was made acidic (pH 3-4) with dilute hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was crystallized from ethanol to afford colorless prisms (1.2 g, 52%), m.p. 144°-146° C.
Reaction SMILES: [C:1]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@H:8]([NH2:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>ClCCl>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21](=[O:22])[NH:10][C@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:12])[CH3:11])=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: C[C@@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of (R)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethylamine (693 mg, 3,66 mmol) (from Example 38a supra) and triethylamine (0.77 mL, 5.5 mmol) (Allied Signal) in dichloromethane was treated with 4-nitrophenyl chloroformate (885 mg, 4.39 mmol) (Aldrich) at room temperature for 30 minutes. The reaction was quenched with 1 N aqueous hydrochloric acid and then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution followed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (15% ethyl acetate in hexanes) to give (R)-[2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-carbamic acid 4-nitro-phenyl ester as a colorless oil that solidified upon standing. (Yield 0.49 g, 38%).
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)#[CH:11]>C(N(CC)CC)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>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:11][C:2]2[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: Cc1ccc(N)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2ccc(F)cc2)n1
Yield: 67.3 %

Procedure:
Following the same procedure as described in Example 1, (2-bromo-6-methyl-pyridin-3-yl)amine (200 mg, 1.07 mmol) reacted with (PPh3)2PdCl2 (36 mg, 0.05 mmol), Cul (10 mg, 0.05 mmol) and 1-ethynyl-4-fluorobenzene (184 μl, 1.07 mmol) in triethylamine (5 ml). The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 164 mg (0.72 mmol, 68%) of (2-(4-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid. The hydrochloride of (2-(4-fluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine was prepared as described in Example 1 to yield after trituration with ethyl acetate 154 mg (0.51 mmol, 71%) of the title hydrochloride as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][NH:41][CH2:42][CH2:43][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: NCCN1CCOCC1
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(-c3ccc(CNCCN4CCOCC4)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), N-(2-aminoethyl)morpholine (0.035 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken for 16 h at room temperature. Additiona portions of 1 N-(2-aminoethyl)morpholine (0.030 mL, 0.23 mmol) and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) were added and the reaction mixture was shaken for 4 days. 1N NaOH (1 mL) was added and the precipitate was collected by filtration and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile-0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 16.6-19.0 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(2-morpholinoethyl)amino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid. (0.014 g, 0.021 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.88 (1H, s), 8.29-8.93 (2H, m), 8.11-8.17 (2H, m), 7.92-7.97 (1H, m), 7.83-7.86 (1H, m), 7.68-7.72 (1H, m), 7.46-7.51 (2H, m), 7.39 (1H, s), 7.34-7.38 (1H, m), 3.90 (3H, s), 3.50-3.52 (4H, m), 2.61-2.62 (2H, m), 2.40-2.50 (2H, obscured by DMSO peak), and 2.27-2.40 (6H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile-0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.96 min. MS: MH+ 665.2.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1Cl
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)/C=C/c3ccccc3Cl)n2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid. LC-MS-conditions 01: tR=0.92 min; [M+H]+=370.04.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[CH:4][N:3]=1.[CH:25]1[C:35]2[CH:34]=[CH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH:30]([C:40]3[C:41](=[O:47])[NH:42][C:43](=[O:46])[NH:44][CH:45]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1>>[CH:25]1[C:35]2[CH:34]=[CH:33][C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[CH:30]([C:40]3[C:41](=[O:47])[NH:42][C:43](=[O:46])[N:44]([C:2]4[N:7]=[C:6]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([C:14]5[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=5)=[CH:4][N:3]=4)[CH:45]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1
Reactant: O=c1[nH]cc(C2c3ccccc3C=Cc3ccccc32)c(=O)[nH]1
Reactant: COC(=O)CSc1nc(Cl)ncc1-c1ccc(CC(=O)OC)cc1
Product: COC(=O)CSc1nc(-n2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)ncc1-c1ccc(CC(=O)OC)cc1

Procedure:
The subtitle compound was prepared from the product of step (iv) (0.58 g) and the product of example 1 step (iv) (0.48 g) by the method of example 2 step (i). Purification was by chromatography eluting with 2% methanol in chloroform. Yield 0.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22]C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Br>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Br
Product: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The crude 1-[1-(4-chlorophenyl)cyclobutyl]-7-methoxy-3,4-dihydroisoquinoline (10.25 g, 30.8 mmol) was treated with 47% aqueous hydrobromic acid (109 mL) and stirred at 120° C. for 4 h. The reaction mixture was cooled to room temperature. The aqueous layer was decanted. The crude product was treated with dichloromethan, methanol and water and the pH was adjusted to 10 with aqueous 1N sodium hydroxide solution. The product precipitated and the solid was collected by filtration. The product was washed with water and dried in vacuo at 30° C. Yield: 3.56 g (30.3, 12.38 mmol).
Reaction SMILES: N#N.CCCCC.Cl[C:9]([F:13])=[C:10]([F:12])[F:11].Cl[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].CCCCCC.C([Li])CCC>CCCCC.C(OCC)C.O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[C:9]([F:13])=[C:10]([F:12])[F:11])[CH3:17]
Reactant: CC[Si](Cl)(CC)CC
Reactant: FC(F)=C(F)Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Si](CC)(CC)C(F)=C(F)F
Temperature: -130 °C
Yield: 84.8 %

Procedure:
A reactor flushed with argon was cooled with a liquid nitrogen-pentane cooling medium, and 15.0 g (0.129 mol) of chlorotrifluoroetylene was fed into the reactor. To this reactor, 50 ml of anhydrous tetrahydrofuran (THF), 30 ml of diethyl ether (Et2O) and 30 ml of pentane were introduced to bring the concentration of chlorotrifluoroethylene to 1 mmol/ml. Then, 16.1 g (0.107 mol) of chlorotriethylsilane was introduced. The reactor was cooled to -130° C., and then 88 ml (0.140 mol) of a hexane solution of butyllithium (1.6M) was introduced over a period of one hour. Then, the temperature was gradually raised to room temperature over 7.5 hours. The reaction solution was filtered and dried through a column of Celite placed on anhydrous sodium sulfate. The solvent was removed, and the residue was distilled, whereby 17.8 g of triethyltrifluorovinylsilane was obtained as a colorless transparent oil (yield: 85.1%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([CH3:11])[CH:5]=1)(=[O:3])[CH3:2].[C:12]1([CH2:18][S:19][CH:20]([C:24](O)=[O:25])[C:21](O)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:10][C:8]1[CH:9]=[C:4]([C:1]2[O:3][C:21](=[O:22])[C:20]([S:19][CH2:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:24]([OH:25])[CH:2]=2)[CH:5]=[C:6]([CH3:11])[N:7]=1
Reactant: CC(=O)c1cc(C)nc(C)c1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)n1

Procedure:
The title compound was prepared from the condensation of the trimethylsilyl enol ether of 4-acetyl-2,6-dimethylpyridine and the diethyl ester of [(phenylmethyl)thio]propanedioic acid following the same procedure outlined in Method A; m.p. 88°-90° C. NMR (DMSO-d6) δ 2.55 (s, 6 H), 4.02 (s, 2 H), 6.85 (s, 1 H), 7.16-7.28 (m, 5 H), 7.40 (s, 2 H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH2:8])[O:6][CH:7]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]([C:27](O)=[O:28])[C:17]3[C:22]([O:23][C:24]=2[CH:25]=1)=[CH:21][C:20]([F:26])=[CH:19][CH:18]=3>>[F:1][C:2]([F:10])([F:9])[C:3]1[N:4]=[C:5]([NH:8][C:27]([CH:16]2[C:17]3[CH:18]=[CH:19][C:20]([F:26])=[CH:21][C:22]=3[O:23][C:24]3[C:15]2=[CH:14][CH:13]=[C:12]([F:11])[CH:25]=3)=[O:28])[O:6][CH:7]=1
Reactant: Nc1nc(C(F)(F)F)co1
Reactant: O=C(O)C1c2ccc(F)cc2Oc2cc(F)ccc21
Product: O=C(Nc1nc(C(F)(F)F)co1)C1c2ccc(F)cc2Oc2cc(F)ccc21

Procedure:
The title compound, white solid, m.p. 265° C. and MS: m/e=397.2 (M+H+), is prepared in accordance with the general method of example 3c from 4-trifluoromethyl-oxazol-2-ylamine and 3,6-difluoro-9H-xanthene-9-carboxylic acid (CAS:[188028-37-7]).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Cl:10][C:11]1[C:16]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 37.9 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 2-chloro-pyridine-3-carboxylic acid (48.6 mg, 0.37 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 90% EtOAc in Hexane as eluent) to afford 65 mg (45.7% yield) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-pyridine-3-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 99.71, 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.5 (d, 1H), 8.0-7.9 (d, 3H), 7.84-7.7 (q, 4H), 7.6-7.46 (m, 3H), 7.44-7.36 (m, 1H), 4.26-4.3 (m, 2H), 3.8-3.58 (m, 4H), 3.58-3.46 (m, 2H), 3.28-3.12 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13]([Br:14])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]([N:20]([CH2:58][CH2:59][CH3:60])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[N:38](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)=[N:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([CH2:7][CH2:8][N:9]2[C:13]([Br:14])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]([N:20]([CH2:58][CH2:59][CH3:60])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)=[N:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Solvent: CCO
Product: CCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Yield: 87.7 %

Procedure:
356 mg of N-[1-(2-phenylethyl)-4-ethoxycarbonyl-5-bromopyrazol-3-yl]-N-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-n-propylamine were dissolved in 5 ml of ethanol and heated under reflux for 2 hours, and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (n-hexane--ethyl acetate=2:1→ethyl acetate) to obtain 224 mg of the intended compound as a pale yellow, amorphous solid.