Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[CH3:28][N:25]1[C:26]2[CH:27]=[C:19]([N:12]3[C:11](=[O:15])[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:4][CH:5]=4)[CH:14]=[N:13]3)[CH:20]=[CH:21][C:22]=2[C:23]2[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][C:24]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cn[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ncc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 30.2 %

Procedure:
5-(4-(Trifluoromethyl)phenyl)pyridazin-3(2H)-one (100 mg, 0.41 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (151 mg, 0.41 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (65 mg, 30%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.59 (d, J=1.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 7.26-7.24 (m, 1H), 4.62 (s, 2H), 3.89-3.80 (br m, 2H), 3.66 (s, 3H), 2.84 (br m, 2H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:20])=[N:17][CH:18]=2)[CH2:4][CH2:3]1.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:37]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:38]([C:36]1[CH:37]=[C:33]([NH:32][C:31]([NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C@H:5]([O:12][C:13]3[CH:18]=[N:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][CH:14]=3)[CH2:4][CH2:3]2)=[O:30])[N:34]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)[N:35]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@@H](Oc2ccc(C(=O)N3CCOCC3)nc2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc(C(=O)N4CCOCC4)nc3)c3ccccc32)cc1
Temperature: 60 °C
Yield: 30 %

Procedure:
Intermediate 17b (234 mg, 0.66 mmol) was dissolved in 1,4-dioxane (7.0 mL) and [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 268 mg, 0.66 mmol) and diisopropylethylamine (229 μL, 1.32 mmol) were added. The reaction mixture was heated to 60° C. for 20 h, then cooled, partitioned between EtOAc (50 mL) and water (50 mL), and extracted into EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (120 mg, 0.20 mmol, 30%). LCMS (Method 5): Rt 4.76 min, m/z=609 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.30 (9H, s), 1.85-2.05 (2H, m), 2.05-2.18 (2H, m), 2.38 (3H, s), 3.57-3.76 (8H, br m), 4.86-4.92 (1H, dd, J 8.6, 5.5 Hz), 5.54-5.57 (1H, t, J 4.3 Hz), 6.33 (1H, s), 7.20-7.34 (9H, m), 7.58-7.65 (2H, m), 8.24-8.26 (1H, dd, J 2.4, 0.8 Hz).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>Cl[Pd]Cl.CN(C=O)C>[CH2:15]([C:14]1[N:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:29]=[C:8]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NNc1ccccc1
Reactant: Clc1ccccc1C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1ccc(Cc2c3ccccc3nn2-c2ccccc2)cc1
Temperature: 130 °C
Yield: 80.9 %

Procedure:
Following the general procedure outlined above, a reaction tube was charged with 4.4 mg PdCl2 (5 mol %), 14.5 mg tBu3PHBF4 (10 mol %), 228.1 mg Cs2CO3 (1.4 equiv.) and 2.5 mL DMF. After stirring for 30 min at RT under a flow of argon, 1-chloro-2-phenylethynyl-benzene (106.3 mg, 1.0 equiv.) and phenylhydrazine (75.7 mg, 1.4 equiv.) were added and the reaction was heated to 130° C. for 3 hours. After cooling to RT, the reaction mixture was quenched with brine (30 mL) and extracted with EtOAc (2×30 mL) and the organic phase was dried by eluting through a Varian Chem Elut 12198007 cartridge. Removal of the solvents afforded the crude indazole as a dark-brown oil that purified by FC on silica using CH2Cl2/EtOAc to afford 115.0 mg (81%) of 3-benzyl-2-phenyl-2H-indazole colorless oil that solidified upon standing. 1H-NMR (DMSO-d6) δ 4.47 (s, 2H), 6.98 (d, 2H, J=7.1 Hz), 7.03 (dd, 1H, J=7.9, 7.0 Hz), 7.13-7.24 (m, 3H), 7.30 (dd, 1H, J=8.1, 7.0 Hz), 7.52-7.58 (m, 5H), 7.60 (d, 1H, J=8.6 Hz), 7.65 (d, 1H, J=8.6 Hz); 13C-NMR (DMSO-d6) δ 30.4, 117.1, 120.5, 121.0, 121.2, 125.9 (2C), 126.3, 126.4, 128.1 (2C), 128.4 (2C), 128.9, 129.2 (2C), 134.5, 137.9, 139.5, 147.9; HRMS (FAB): Calculated for C20H17N2 (M+H+) 285.1391, found 285.1385.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([Mg]Br)[CH:10]=[CH2:11]>C(OCC)C.[Cu](Cl)(Cl)(Cl)Cl.[Li].[Li]>[CH2:11]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: C=CC[Mg]Br
Reactant: Brc1ccc(I)cc1
Agent: Cl[Cu](Cl)(Cl)Cl
Agent: [Li]
Solvent: CCOCC
Product: C=CCc1ccc(Br)cc1

Procedure:
To a mixture comprising 4-bromo-iodobenzene (350 mmol), dilithium copper tetrachloride (15 mmol), and 500 ml of diethyl ether, was added dropwise 1M solution of allyl magnesium bromide on the market (corresponding to 300 mmol) in diethyl ether at a temperature lower than 10° C. in 2 hours. The solvent was removed under a reduced pressure and the residue was distilled under a reduced pressure to obtain a crude oily 4-allyl-bromobenzene. This product was rectified with an Oldershow column (number of theoretical plates is 10) to obtain 4-allyl-bromobenzene (127 mmol) as the distillate at 130°-134° C./9 mmHg.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[Br:8][C:9]1[C:10](O)=[C:11]([C:17]([CH3:20])=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:8][C:9]1[C:10]([O:6][CH3:7])=[C:11]([C:17]([CH3:20])=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)c1c(C)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)ccc(Br)c1OC
Temperature: 25 °C

Procedure:
Dimethyl sulphate (2.3 ml) was added to a suspension of ethyl 3-bromo-2-hydroxy-6-methylbenzoate (Intermediate 92, 5.19 g) and potassium carbonate (5.64 g) in dry acetone (70 ml) and the resultant mixture was stirred and heated at reflux for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ether and washed with NaHCO3 (saturated aqueous solution), dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give crude ethyl 3-bromo-2-methoxy-6-methylbenzoate (5.4 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1)[CH3:30].C(N(CC)CC)C.O>ClCCl>[CH2:29]([O:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40]([N:11]2[CH2:12][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:28])[C@:9]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[F:27])([C:18]#[N:19])[C@@H:10]2[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:41])=[CH:35][CH:34]=1)[CH3:30]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)N2C[C@H](c3cccc(Cl)c3F)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile prepared in Example 3 (0.44 g, 1.04 mmol) in dichloromethane (5 mL) was added 4-isocyanato-benzoic acid ethyl ester (Aldrich, 0.22 g, 1.14 mmol) and triethylamine (0.22 mL, 1.56 mmol). The reaction mixture was stirred at room temperature for 30 min. Water was added, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (25% EtOAc in hexanes) to give rac-4-{[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid ethyl ester as a white solid (0.59 g, 92%)
Reaction SMILES: [NH:1]([C:5]1[CH:34]=[CH:33][C:8]2[NH:9][C:10]([CH:12]([C:14]3[NH:15][C:16]4[CH2:21][CH2:20][N:19](C(OCC5C=CC=CC=5)=O)[CH2:18][C:17]=4[N:32]=3)[CH3:13])=[N:11][C:7]=2[CH:6]=1)[C:2]([NH2:4])=[NH:3].O1CCCC1>[Pd].CO>[NH:15]1[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=2[N:32]=[C:14]1[CH:12]([C:10]1[NH:9][C:8]2[CH:33]=[CH:34][C:5]([NH:1][C:2]([NH2:4])=[NH:3])=[CH:6][C:7]=2[N:11]=1)[CH3:13]
Reactant: CC(c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2)c1nc2cc(NC(=N)N)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(c1nc2c([nH]1)CCNC2)c1nc2cc(NC(=N)N)ccc2[nH]1
Yield: 96.7 %

Procedure:
A mixture comprising benzyl 2-[1-(5-guanidino-1H-benzoimidazol-2-yl)ethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (1.0 g, 2.2 mmol), 10% palladium on carbon (0.5 g), tetrahydrofuran (50 mL) and methanol (50 mL) was hydrogenated at one atmosphere, filtered and concentrated in vacuo to provide N-{2-[1-(4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-2-yl)ethyl]-1H-benzoimidazol-5-yl)-guanidine (0.69 g, 97% yield); LRMS(ESI): Calculated for C16H20N8: 324.4; Found (MH+): 325.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1cccc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1cccc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
To a stirred solution of 2.99 g (8.90 mmole) of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 27 mL of acetone and 27 mL of water was added 2.97 g (45.15 mmole) of sodium azide. The mixture was heated at 70 degrees for 11 hours. The mixture was partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 60 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.97 g of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[O:16])[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[NH2:33][C@@H:34]([CH:49]([CH3:51])[CH3:50])[C:35]([O:37][C@H:38]([CH:47]=[CH2:48])[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:36].O>CN(C)C=O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:33][C@@H:34]([CH:49]([CH3:51])[CH3:50])[C:35]([O:37][C@H:38]([CH:47]=[CH2:48])[CH2:39][C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])=[O:36])=[O:21])=[O:16])[N:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C[C@H](CC(=O)OC(C)(C)C)OC(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)NCc1nc(C(=O)NC(C)(C)C(=O)O)cs1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@H](CC(=O)OC(C)(C)C)OC(=O)[C@@H](NC(=O)C(C)(C)NC(=O)c1csc(CNC(=O)OC(C)(C)C)n1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a solution of 2-(2-((tert-butoxycarbonylamino) methyl)thiazole-4-carboxamido)-2-methylpropanoic acid (1.26 g, 3.67 mmole) in 10 mL Dimethylformamide was added HBTU(O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate) (1.67 g, 4.40 mmole) and diisopropylethylamine (2.0 mL, 11.0 mmole). The resulting reaction mixture was stirred at room temperature for 10 minutes. (S)-tert-butyl 3-((S)-2-amino-3-methylbutanoyloxy)pent-4-enoate (1.0 g, 3.67 mmole) was added, and the resulting mixture was stirred overnight. Water and EtOAc were added and the layers were separated. The aqueous layer was extracted with EtOAc, the combined organic layer was dried over Na2SO4 and concentrated. It was purified by column chromatography, eluted with 1:1 Hex/EtOAc to get the desired product (2.1 g, 96% yield).
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.Br[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1>>[CH3:27][C:24]1[N:25]=[CH:26][C:21]([CH2:20][CH2:19][N:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=2)[NH2:16])=[CH:22][CH:23]=1
Reactant: Cc1ccc(CCBr)cn1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by General Method 1. Triethylamine (13.0 mL, 94.5 mmol) was added dropwise to p-tolylhydrazine hydrochloride (5.0 g, 31.5 mmol) over a period of 5-min. The reaction mixture was stirred for additional 10 min. 5-(2-bromoethyl)-2-methylpyridine (6.3 g, 31.5 mmol) was added dropwise at 25° C. over a period of 10-15 min. The reaction mixture was stirred at RT for 1 h and the subsequently heated at 90° C. for 2-3 h at which point the reaction was found complete by TLC and LC-MS. Reaction mixture was concentrated under reduced pressure and diluted with water (50 mL) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain crude product as dark brown oil (16.7 g). Purification of crude product by column chromatography (silica gel, 100-200 mesh, eluent: 0-40% ethyl acetate-Hexane) furnished 1.92 g of pure product as brown liquid. Yield: 25%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1([CH2:13][CH2:12][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[CH3:9])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1cc(Br)ccc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1OCCN1CCCC1

Procedure:
4-Bromo-2-methylphenol (10 g, 53.5 mmol) and 1-(2-chloroethyl)pyrrolidine HCl (11 g, 64.7 mmol) were heated at 80° C. in 500 mL of DMF in the presence of K2CO3 (22 g, 159.2 mmol) for 16 h. After cooling, the crude product was filtered and concentrated in vacuo. The brown oily residue was purified by PrepLC (SiO2; gradient of 90:8:2 to 85:10:5 hexanes-THF-TEA) to afford 11.25 g (39.6 mmol; 74%) of the title compound as a clear, colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1cccc(Br)c1
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of 2-(3-bromophenyl)ethanol (9.0 g, 0.044 mol) in DCM (300 mL), Dess-Martin reagent (38.0 g, 0.090 mol) was added in portions. The reaction mixture was stirred overnight, and filtered. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1) to afford 2-(3-bromophenyl)acetaldehyde (5.0 g, 55%) as a yellow oil. MS (ES+) C8H7BrO requires: 198, 200 found: 199 [M+H]+, 201 [M+2+H]+(1:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@@H:14]([OH:16])[CH3:15])[CH:6]=1.C(N(CC)CC)C.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>ClCCl.CCCCCC>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C@@H:14]([O:16][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH3:15])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Cc1cccc(OCC[C@H](C)O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Cc1cccc(OCC[C@H](C)OS(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a stirring solution of (S)-[3-(3-hydroxy-butoxy)-phenyl]-acetic acid methyl ester (589 mg, 2.47 mmol) and triethylamine (376 mg, 3.71 mmol) in dichloromethane (10 mL) at 0° C. was added p-toluenesulfonyl chloride (944 mg, 4.95 mmol). The reaction was then stirred at RT for 30 min. and refluxed overnight. The reaction mixture was poured into H2O (40 mL) and extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% EtOAc:hexane as eluent to afford 0.61 g (63% yield) of the title compound as an oil: MS (ESI) 393.0 (M+H+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[Cl:23].C1(N)CCCCC1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)(Cl)Cl.[Cu](I)I.CO.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[Cl:23])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: Clc1ccncc1Br
Agent: I[Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1Cl
Yield: 59.2 %

Procedure:
Using the same reaction conditions and work up as described in Example 1, step-3,1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 800 mg, 3.653 mmol) was refluxed with 3-bromo-4-chloro-pyridine (879 mg, 4.566 mmol), copper iodide (70 mg, 0.365 mmol), cyclohexane-1,2-diamine (125 mg, 1.0958 mmol), potassium phosphate (2.32 g, 10.958 mmol) and 1,4-Dioxane (50 mL) at 110° C. for 12 hours to afford the crude product. The reaction was monitored by TLC (10% MeOH in chloroform). Purification by column chromatography on silica gel (1.5% methanol in chloroform) afforded 715 mg of the product (60% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:13][CH2:14][CH2:15][OH:16])=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)N>>[CH3:17][C:18]1[CH:19]=[C:20]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([O:13][CH2:14][CH2:15][OH:16])[C:3]=23)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CN(C)C=Nc1[nH]nc(OCCO)c1C#N
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCO)c23)ccc1OCc1ccccn1
Yield: 89.8 %

Procedure:
The procedure described in Example 1 was repeated using N′-[4-cyano-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-N,N-dimethylimidoformamide (200 mg, 0.9 mmol) and 3-methyl-4-(pyridin-2-ylmethoxy)aniline (231 mg, 1.08 mmol) to give the title compound as a white solid (317 mg, 90%); NMR Spectrum: 2.27 (s, 3H), 3.79 (s, 2H), 4.30 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.35 (dd, 1H), 7.40 (s+d, 2H), 7.74 (d, 1H), 7.84 (t, 1H), 8.21 (s, 1H), 8.33 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 393 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([NH2:8])[CH3:7].[CH3:20][C:21]([C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])=[CH2:22]>CO>[CH3:1][CH:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([N:8]1[CH2:25][CH:24]([CH3:26])[C:23](=[O:27])[CH:21]([CH3:22])[CH2:20]1)[CH3:7]
Reactant: C=C(C)C(=O)C(=C)C
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)N
Solvent: CO
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)N1CC(C)C(=O)C(C)C1
Temperature: 65 °C
Yield: 89 %

Procedure:
53.9 parts by weight of 6,10,14-trimethyl-2-amino-pentadecane are dissolved in 200 parts of methanol. A solution of 22 parts of 2,4-dimethyl-penta-1,4-dien-3-one in 100 parts of methanol is added at room temperature and this mixture is then heated at the reflux temperature (65° C.) for 3 hours. The reaction product is worked up by distillation, giving 67.5 parts ( 89% of theory) of N-(6,10,14-trimethyl-pentadec-2-yl)-3,5-dimethyl-piperidin-4-one, boiling point=171° C./0.01 mm Hg (active ingredient No. 20).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CCO>[CH:1]1([NH:4][C:5]2[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC2CC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(NC2CC2)nc1

Procedure:
A mixture of 332 (0.71 g, 3.44 mmol, 1M NaOH (6.89 mL, 6.89 mmol) and EtOH (10 mL) was stirred and heated to 80° for 2 h. The solvent was evaporated and the residue dissolved in H2O and the pH adjusted to ca. 2. The resulting precipitate was filtered, washed with water, air dried. to afford 168 mg of 6-cyclopropylamino-nicotinic acid (334) as a white powder.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.[Br:41]N1C(C)(C)C(=O)N(Br)C1=O.[O-]S([O-])=O.[Na+].[Na+]>CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=4[F:39])=[O:27])=[C:21]([F:40])[CH:20]=3)[C:14]([CH2:16][O:17][CH3:18])=[C:15]([Br:41])[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c(F)c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c2c(N)ncnn2c1Br
Temperature: -40 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To a solution of THF (500 mL) was added 1-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (2.29 g, 4.65 mmol). The solution was cooled to −40° C. and then 1,3-dibromo-5,5-dimethylhydantoin (665 mg, 2.33 mmol) was added in two batches 20 min apart. The reaction was stirred at −40° C. for 1 h and then allowed to warm to rt over the following 2 h. Aq saturated Na2SO3 was added to the reaction followed by EtOAc. The layers were separated and the aqueous layer was back extracted with EtOAc. The organic layer was washed with 1N NaOH and water, dried (Na2SO4), filtered and evaporated to yield 2.83 g crude (107%) of the desired product. MS [M+H]+=571; LCMS RT=3.54.