Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([N:18]1[C:26]2[CH2:25][CH2:24][CH2:23][C:22](=[O:27])[C:21]=2[CH:20]=[N:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:28](Cl)(=[O:30])[CH3:29]>O1CCCC1>[C:28]([CH:23]1[CH2:24][CH2:25][C:26]2[N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:19]=[CH:20][C:21]=2[C:22]1=[O:27])(=[O:30])[CH3:29]
Reactant: O=C1CCCc2c1cnn2Cc1ccccc1
Reactant: CC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1CCc2c(cnn2Cc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 321 ml of 1.0 N lithium bis(trimethylsilyl)amide in 350 ml of anhydrous tetrahydrofuran maintained at -78° C, there was added dropwise a solution of 33 g of 1-benzyl-1,5,6,7-tetrahydro-4H-indazol-4-one in 150 ml of anhydrous tetrahydrofuran. The mixture was stirred at -78° C. for 10 minutes and then a solution of 11.4 g of acetyl chloride in 120 ml of anhydrous tetrahydrofuran was added. The reaction mixture was worked up in the same manner as described in the first paragraph of this example to give 5-acetyl-1-benzyl-1,5,6,7-tetrahydro-4H-indazol-4one as a yellow oil which crystallized on standing.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[CH3:13][C:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:25]([O-])=O)[NH:16][CH:15]=1>>[NH2:25][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[C:23](=[O:24])[C:14]([CH3:13])=[CH:15][NH:16]2
Reactant: Cc1c[nH]c2cccc([N+](=O)[O-])c2c1=O
Agent: CNC(=O)c1cc(F)ccc1N
Product: Cc1c[nH]c2cccc(N)c2c1=O

Procedure:
The title compound was prepared according to procedure for 2-Amino-5-fluoro-N-methylbenzamide (Compound 102A) using 3-methyl-5-nitroquinolin-4(1H)-one (Eur J Med. Chem. 1992, 37, 547-570). 1H NMR (DMSO-d6, 400 MHz): δ=1.87 (d, J=0.76 Hz, 3 H), 6.21 (dd, J=7.83, 1.01 Hz, 1 H), 6.40 (dd, J=8.08, 1.01 Hz, 1 H), 7.12 (t, J=8.08 Hz, 1 H), 7.62 (dd, J=5.94, 0.88 Hz, 1 H), 11.19 (d, J=5.05 Hz, 1 H). MS (ES+): m/z 175.07 [MH+] (TOF, polar).
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])=[O:5])C.C(O)=O>C(O)C.O>[C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1cccc(O)c1=O
Solvent: CCO
Solvent: O=CO
Solvent: O
Product: O=C(O)Cn1cccc(O)c1=O
Temperature: 60 °C
Yield: 81.6 %

Procedure:
1-Ethoxycarbonylmethyl-3-hydroxypyrid-2-one (2 g) is dissolved in 15 ml of 1:2 v/v ethanol/water containing sufficient ammonium hydroxide to create a pH of 12.0. The solution is heated at 60° C. for 30 minutes, cooled, and acidified to pH 3.0 by the addition of formic acid. The solution is rotary evaporated to remove most of the ethanol and then freeze dried for 20 hours to remove the water, formic acid and ammonium formate. The resulting solid is recrystallised from water to yield white crystals (1.4 g), m.p. 203°-205° C.; νmax (nujol) 1540, 1590, 1640, 1695, 3240 cm-1 ; δ(d6DMSO) 4.5 (s, 2H), 5.95 (t, 1H), 6.6 (d, 1H), 7.0 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][C@H:26]2[CH2:39]OS(C)(=O)=O)=[CH:21][C:20]=1[F:45]>COCCOC>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:27][C@H:26]2[CH2:39][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:1])=[CH:21][C:20]=1[F:45]
Reactant: COC(=O)c1cccnc1O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cccn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
Methyl 2-hydroxypyridine-3-carboxylate (1.48 g) and potassium carbonate (2.23 g) were added to a solution of tert-butyl (6S,7R)-7-(4-chloro-3-fluorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (3.53 g) in 1,2-dimethoxyethane (70 ml). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.88 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[C:12]([CH3:13])=[N:11][C:10]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)=[N:9]2)=[CH:5][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CS(C)=O>[CH3:13][C:12]1[N:8]([CH2:7][C:4]2[S:3][C:2]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:6][CH:5]=2)[N:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:15]=2)[N:11]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cnc(Cl)s1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cnc(N2CCOCC2)s1
Temperature: 140 °C
Yield: 42.6 %

Procedure:
5-(1-((2-Chlorothiazol-5-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoro methoxy)phenyl)-1,2,4-oxadiazole (45 mg, 0.1 mmol) was mixed with morpholine (87 mg, 1.0 mmol) in DMSO (0.5 mL). The mixture was heated to 140° C. overnight. The resulting crude product was purified by a silica gel column with (EtOAc/Hexane 50% to 100% EtOAc) to give 4-(5-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)thiazol-2-yl)morpholine as a white solid (21 mg, 43%). MS (ES+) C20H18F3N7O3S requires: 493. found: 494[M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.24 (s, 1H), 5.47 (s, 2H), 3.78 (t, J=4.9 Hz, 4H), 3.44 (t, J=4.9 Hz, 4H), 2.62 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1.C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:23]([OH:26])[OH:24])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCOc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 27 (14.70 g, 0.066 mol) in anhydrous THF (140 ml), n-butyllithium (30 ml, 2.5M in hexane, 0.075 mol), trimethyl borate (13.72 g, 0.132 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:13]#[N:14].[NH2:15][NH2:16]>CS(C)=O>[CH3:12][C:7]1[N:6]=[C:5]2[S:4][C:3]3[C:13]([NH2:14])=[N:16][NH:15][C:2]=3[C:10]2=[C:9]([CH3:11])[CH:8]=1
Reactant: Cc1cc(C)c2c(Br)c(C#N)sc2n1
Reactant: NN
Solvent: CS(C)=O
Product: Cc1cc(C)c2c(n1)sc1c(N)n[nH]c12
Temperature: 25 °C
Yield: 99.8 %

Procedure:
The 3-bromo-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile (1.11 g, 4.17 mmol) was added to a microwave reaction vial. The DMSO (14 mL) was added, followed by hydrazine (0.392 mL, 12.5 mmol). The vial was sealed and irradiated at 150 degrees for 10 minutes. LCMS showed no remaining starting material. The reaction was cooled to RT, then poured into 150 mL of ice-water. The ice was allowed to melt and resulting slurry was poured through filter paper, washing the solid with cold water (3×). The solid was then dried under vacuum at 60° C. to give 908 mg (98%) of the product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.07 (s, 1H), 5.35 (bs, 2H), 2.62 (s, 3H), 2.49 (s, 3H). LC/MS: RT=0.38 min., m/z=219.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[Br:55][C:56]1[CH:57]=[N:58][CH:59]=[C:60](Br)[CH:61]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[Br:55][C:56]1[CH:61]=[C:60]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:59]=[N:58][CH:57]=1
Reactant: O=C1CCCN1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCCN1c1cncc(Br)c1
Yield: 44.2 %

Procedure:
Cesium carbonate (213 mg), pyrrolidin-2-one (45 mg), Xantphos (76 mg), and Pd2(dba)3 (60 mg) were added to a 1,4-dioxane (4 ml) solution containing 3,5-dibromopyridine (100 mg) in a nitrogen atmosphere, followed by reflux for 4 hours. The reaction mixture was adjusted to room temperature and water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1 to 1:1), and a white solid of 1-(5-bromopyridin-3-yl)pyrrolidin-2-one (45 mg) was thus obtained.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:18]([NH2:21])[C:19]#[CH:20].C(OCC)(=O)C>ClCCl>[CH2:18]([NH:21][C@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:19]#[CH:20]
Reactant: C#CCN
Reactant: O[C@H]1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#CCN[C@@H]1CCc2ccccc21
Temperature: 25 °C
Yield: 62.2 %

Procedure:
Methanesulfonyl anhydride (3.0 g, 17.2 mmol) as a solution in dichloromethane (8 mL+4 mL) was added to a stirred solution of (S)-1-indanol (1.02 g, 7.6 mmol) and triethylamine (4.4 mL, 31.5 mmol) in dichloromethane (20 mL) at −26° C. (internal, −35° C. external) over 10 minutes. During the addition the internal temperature rose to −20° C. The reaction was maintained at −29° C. (internal, −35° C., external) for 45 minutes before propargylamine (5 mL, 78 mmol) was added over 2 minutes. The reaction was allowed to warm slowly to room temperature overnight before being portioned between ethyl acetate (50 mL) and ice-water (75 mL, pH of solution 9.7). The organic layer was concentrated under reduced pressure to afford a brown oil which was partitioned between methyl tert-butyl ether (50 mL) and aqueous hydrochloric acid (1M, 40 mL, pH of solution <1). The aqueous layer was basified to pH>12.5 by addition of aqueous sodium hydroxide solution (2M, 30 mL) before being extracted with ethyl acetate (50 mL+30 mL). The combined final organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound as a brown liquid (0.81 g, 68%). Analysis of this material by chiral GC indicated it to be 46% e.e.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[N:12]1([CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][CH:18]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(OCCCN2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OCCCN2CCCCC2)cc1
Reaction time: 18 h

Procedure:
A mixture of 1-[3-(4-nitrophenoxy)propyl]piperidine (15.5 g, 58.6 mmol) and 10% Pd/C (12.5 g) in 150 mL of EtOH was placed under a balloon of H2. The mixture was stirred for 18 h. The catalyst was removed by suction filtration and the organics concentrated to give the title compound as a yellowish oil. MS (m/z)=235.2 (M+H+); Calc'd for C14H22N2O=234.34.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].[C:43]([NH:50][CH2:51][CH:52]=O)([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CO.CC(O)=O>[CH2:1]([N:8]([CH2:52][CH2:51][NH:50][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:14]2[C:13]2[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:12]=2[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NCc1ccccc1)COc1cc(F)ccc1-3
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(CCNC(=O)OC(C)(C)C)Cc1ccccc1)COc1cc(F)ccc1-3
Temperature: 25 °C
Yield: 71 %

Procedure:
To the solution of methyl (7R)-7-(benzylamino)-14-cyclohexyl-3-fluoro-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate in MeOH/HOAc containing NaCNBH3 from the previous step was added N-Boc-2-aminoacetaldehyde (1.5 eq) and the solution was stirred at RT. After 1 h all volatiles were evaporated. The residual material was taken up with EtOAc and the resulting solution was washed with sat. aq. NaHCO3 and brine. After drying over Na2SO4 all volatiles were evaporated in vacuo. The yellow residue was subjected to FC (PE:EtOAc, 8:2+1% NEt3). After evaporation of the solvents the product was obtained as a colourless solid (71%). (ES+) m/z 656 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:40]=[CH:39][C:20]3[N:21]([CH2:35][CH2:36][O:37][CH3:38])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:34].[ClH:34].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]2[CH:40]=[CH:39][C:20]3[N:21]([CH2:35][CH2:36][O:37][CH3:38])[C:22]([NH:24][C:25]4[S:26][C:27]5[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=5[N:29]=4)=[N:23][C:19]=3[CH:18]=2)=[O:16])[CH2:12][CH2:13]1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Yield: 295 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (150 mg) was prepared by following General Procedure L starting from 4-{[2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (160 mg) in 4M HCl in dioxane (2 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:33][CH3:34])[C:31]=1[CH3:32])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:12][C:11]=1[NH:22]C(=O)C(F)(F)F)=[O:7].[CH2:35](I)[CH:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.CO.O>[CH2:35]([NH:22][C:11]1[CH:12]=[C:13]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:29]=[C:30]([O:33][CH3:34])[C:31]([CH3:32])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:36]([CH3:38])[CH3:37]
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NC(=O)C(F)(F)F)cc(OC)c1C
Reactant: CC(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCC(C)C)cc(OC)c1C
Temperature: 85 °C
Yield: 54.3 %

Procedure:
A suspension of compound 1h (200 mg, 0.42 mmol), isobutyl iodide (0.144 mL, 1.25 mmol), and potassium carbonate (173 mg, 1.25 mmol) in DMF (2 mL) was sealed in a pressure tube and heated at 85° C. for three days. Additional portions of isobutyl iodide (3 eq) were added each day. The reaction mixture was cooled to rt, diluted with ethyl acetate, washed with water and brine, dried, and concentrated on a rotary evaporator. The residue was dissolved in a mixture of methanol (10 mL) and water (1 mL), and potassium carbonate (200 mg, 1.45 mmol) was added. The reaction mixture was heated at 50° C. for 2 h. The reaction mixture was diluted with water, filtered, and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (35% v/v ethyl acetate/hexane) to give compound 7a (100 mg, 54%) as a pale yellow solid. ESI-MS m/e 439.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)[CH:6]=1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32](B4OC(C)(C)C(C)(C)O4)[CH:33]=3)[N:28]([C:44]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:27]=2)=[CH:22][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:2]4[CH:3]=[N:4][N:5]([CH:7]5[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]5)[CH:6]=4)[CH:33]=3)[N:28]([C:44]([C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[N:27]=2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2cc(Br)cn2)C1
Reactant: CC1(C)OB(c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(n2cc(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1
Temperature: 80 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
To tert-butyl 3-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.66 g, 2 mmol) and 3-(pyridin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-indazole (1.13 g, 2 mmol) in dioxane (8 mL) and water (2 mL) was added potassium phosphate (848 mg, 4 mmol) and PdCl2(dppf) (120 mg, 0.16 mmol). The reaction mixture was stirred at 80° C. for 24 h. After filtered through a pad of celite, and washed with EtOAc, the filtrate was washed with brine, dried and concentrated. The crude mixture was column purified with mixture of methanol, dichloromethane and ammonia to give tert-butyl 3-(4-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (420 mg) as light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:37]1([C:43]#[CH:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1.[Cu]I.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>[C:1]([O:5][C:6]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:44]#[C:43][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[C:9]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(I)cc2)n1C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(-c2ccc(C#Cc3ccccc3)cc2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-tert-butoxycarbonylamino-5-(4-iodophenyl)imidazole-1-carboxylic acid tert-butyl ester (0.100 g, 0.206 mmol) was dissolved in anhydrous THF (8 mL) and to this solution was added DIPEA (0.359 mL, 2.06 mmol), CuI (0.004 g, 0.021 mmol), and PdCl2(PPh3)2 (0.014 g, 0.021 mmol). The solution was then degassed at ambient temperature for 10 minutes. During this time a solution of the phenyl acetylene (0.105 g, 1.03 mmol) in anhydrous THF (3 mL) was also degassed. The solution of alkyne was added drop-wise to the solution of aryl iodide and the reaction was stirred at room temperature for 12 h. The reaction was filtered through a Celite® pad and the filter cake rinsed with EtOAc (10 mL). The filtrate was washed with sat. NH4Cl (2×10 mL), brine (2×10 mL), and dried (Na2SO4). Filtration and evaporation afforded the crude product which was purified via flash column chromatography (10-50% EtOAc/Hexanes) to obtain 0.085 g (90%) of the target 2-tert-butoxycarbonylamino-5-(4-phenylethynylphenyl) imidazole-1-carboxylic acid tert-butyl ester as a yellow solid: mp=131-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.00 (s, 1H), 7.86 (d, 2H, J=7.6 Hz), 7.42-7.57 (m, 7H), 1.58 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ 152.9, 146.8, 139.9, 136.3, 133.0, 131.7, 131.4, 128.8, 124.9, 122.4, 126.8, 120.9, 113.7, 89.9, 89.5, 85.4, 80.1, 27.9, 27.3; HRMS (ESI) calcd for C27H19N3O4Na (MNa+) 482.2050. found 482.2051.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([CH3:44])=[N:22][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:24]=4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Cl.C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([CH3:44])=[N:22][NH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1n[nH]cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Reaction time: 2.33 h

Procedure:
A suspension of 4-(4-chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine (178 mg, 0.30 mmol) in 5N hydrochloric acid (5 mL), THF (5 mL) and methanol (5 mL) was stirred for 140 minutes. The organic solvents were removed in vacuo then the resulting solution was diluted with 2N HCl and washed with ether. The aqueous phase was basified by addition of sodium hydroxide pellets then extracted with ethyl acetate. This organic extract was washed with brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) and dichloromethane. The product was further purified by preparative HPLC to give the title compound which was converted to its dihydrochloride salt (84 mg, 80%); LCMS (PS-A3) Rt 6.86 min [M+H]+352. 1H NMR (Me-d3-OD) δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H, m), 7.35-7.41 (4H, m), 7.47-7.54 (4H, m), 8.32 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([NH2:32])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH3:20]>C1COCC1.CCOCC>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:32][C:24]3[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=[C:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH:23]=3)=[O:17])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=C=Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: CN(C)Cc1cc(N)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1cc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-6-(4-isocyanato-phenoxy)-pyrimidine (Stage 135.1; 594 mg; 2.40 mmol) in THF (2 ml) is mixed under a N2-atmosphere with a solution of 3-dimethylaminomethyl-5-trifluoromethyl-phenylamine (Stage 135.2; 524 mg; 2.40 mmol) in ether (10 ml). Stirring at rt affords the title compound: MS: [M+1]+=466.