Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1([C:13]([C:15]2(Br)[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]2CCCCl)=[O:14])[CH:7]=[CH:6]C(Cl)=CC1CCCCl.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.CO>C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]([C:2]2([O:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH2:7][CH2:6]2)=[O:14])=[CH:20][CH:19]=1
Reactant: O=C(C1(Br)C=CC(Cl)=CC1CCCCl)C1(Br)C=CC(Cl)=CC1CCCCl
Reactant: Oc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)C1(Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 14.8 g=50 mmol of 1-bromo-3-chloropropyl4-chlorophenyl ketone in 30 ml of acetonitrile was added dropwise at room temperature with stirring to a suspension of 17.2 g=125 mmol of powdered potassium carbonate and 6.4 g=50 mmol of p-chlorophenol in 60 ml of acetonitrile. The mixture was stirred for 5 hours at room temperature, 0.4 g of tetrabutylammonium bromide was added, and the mixture was refluxed for 10 hours and worked up as specified in Example 1, and 12.6 g (82% of theory) of melting point: 69°-71° C. (from methanol) were obtained.
Reaction SMILES: [Cl-].[Cl-].[Ca+2:3].[P:4](=[O:8])([OH:7])([OH:6])[OH:5].FF.[Na+].[Cl-]>O>[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:3].[P:4]([O-:8])([O-:7])([O-:6])=[O:5].[Ca+2:3].[Ca+2:3]
Reactant: O=P(O)(O)O
Agent: FF
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 160 °C

Procedure:
An aqueous solution of calcium dichloride was mixed with phosphoric acid of high fluorine content to produce a solution having a Ca/P mole ratio of 0.8 and a solution P/F ratio of about 20. The solution was treated with NaCl and chilled to produce a precipitate in accordance with the procedure of Example 1(a). The slurry was filtered yielding a filtrate having a Ca/P mole ratio of 0.8 and a P/F ratio of about 60. The solution was then fed to a conventional spray dryer at a rate of about 125 ml./min., with the exit gas temperature of the dryer being maintained at about 320°F. The dried product had a P/F ratio in excess of 100 and comprised a mixture of CaHPO4, CaClH2PO4 . H2O, and Ca(H2PO4)2.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:29])[C@@H:12]([NH:14][C:15](=[O:28])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]([CH3:19])[CH3:18])[CH3:13])[NH:6]1)=O.O.[OH-].[Li+].Cl.[CH:34]([C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][C:42]([C@H:46]([OH:48])[CH3:47])=[N:43]2)=[CH:38][CH:37]=1)=[CH2:35].Cl.CN(C)CCCN=C=NCC>O1CCCC1.ClCCl.CN(C)C1C=CN=CC=1.O>[CH:34]([C:36]1[CH:45]=[C:44]2[C:39]([CH:40]=[CH:41][C:42]([C@H:46]([O:48][C:3]([C@@H:5]3[CH2:10][CH2:9][CH2:8][N:7]([C:11](=[O:29])[C@@H:12]([NH:14][C:15](=[O:28])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH:17]([CH3:19])[CH3:18])[CH3:13])[NH:6]3)=[O:2])[CH3:47])=[N:43]2)=[CH:38][CH:37]=1)=[CH2:35]
Reactant: COC(=O)[C@@H]1CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N1
Reactant: C=Cc1ccc2ccc([C@@H](C)O)nc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C=Cc1ccc2ccc([C@@H](C)OC(=O)[C@@H]3CCCN(C(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N3)nc2c1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
(S)-1-[(S)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid methyl ester (562 mg, 1.36 mmol) was suspended in tetrahydrofuran (14 mL) then lithium hydroxide monohydrate (63 mg, 1.49 mmol) and water (3 mL) were added. The mixture was rapidly stirred for 30 minutes and then hydrochloric acid (2 M, 0.68 mL) was added. The mixture was evaporated and the residue was then suspended in anhydrous dichloromethane (13.5 mL) with 4 Å molecular sieves (powdered, 2 g). To the stirred mixture, under nitrogen, was added (R)-1-(7-vinyl-quinolin-2-yl)-ethanol (271 mg, 1.36 mmol) in anhydrous dichloromethane (13.5 mL), followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (366 mg, 1.90 mmol) and 4-dimethylaminopyridine (166 mg, 1.36 mmol) and the resulting mixture was stirred for 16 h. A further portion of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol) and 4-dimethylaminopyridine (83 mg, 0.68 mmol) were then added and the reaction mixture stirred for a further 5 h. The mixture was filtered through Celite and the filtrate washed with saturated aqueous ammonium chloride solution, followed by water and then brine. The organics were dried over anhydrous sodium sulfate, filtered and the filtrate evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:3 to 1:1 to afford the title compound (366 mg, 46%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 0.86-1.00 (m, 6H), 1.33 (d, J=6.7 Hz, 3H), 1.46 (s, 9H), 1.52-1.61 (m, 1H), 1.74 (d, J=6.7 Hz, 3H), 1.84-2.27 (m, 4H), 2.74-2.88 (m, 1H), 3.58-3.69 (m, 1H), 3.74-3.87 (m, 1H), 3.91-4.02 (m, 1H), 4.41-4.51 (m, 1H), 5.06-5.16 (m, 1H), 5.29 (app pentet, J=6.9 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 5.97 (d, J=17.6 Hz, 1H), 6.13 (q, J=6.7 Hz, 1H), 6.73 (d, J=7.1 Hz, 1H), 6.94 (dd, J=17.8, 10.7 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.69 (dd, J=8.5, 1.3 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.18 (d, J=8.5 Hz, 1H). LCMS (m/z) 582.2 [M+H], Tr=2.58 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[NH2:12].C1(C)C=CC=CC=1.CC(C)([O-])C.[Na+]>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].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.O>[Cl:9][C:10]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:11]=1[NH:12][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1
Reactant: Nc1cc(F)ccc1Cl
Reactant: Fc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(Nc2cc(F)ccc2Cl)cc1
Temperature: 110 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
A round bottom flask was charged with 1-bromo-4-fluorobenzene (4.809 g, 27.5 mmol), 2-chloro-5-fluoroaniline (4.000 g, 27.5 mmol), Xantphos (0.636 g, 1.1 mmol), anhydrous toluene (100 mL), and sodium tert-butoxide (3.961 g, 41.2 mmol). The mixture was degassed and filled with argon, and then tris(dibenzylideneacetone)dipalladium(0) (0.755 g, 0.8 mmol) was added and the reaction was stirred under argon at 110° C. for 5 hrs. After cooling to room temperature, the mixture was treated with water and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-20% ethyl acetate/hexanes) to afford the product as a colorless oil (5.75 g, 87%). 1H NMR (300 MHz, CDCl3) δ 7.27 (dd, 1H, J=9.0, 5.4 Hz), 7.23-7.03 (m, 4H), 6.71 (dd, 1H, J=10.8, 2.4 Hz), 6.47 (td, 1H, J=8.1, 3.0 Hz), 6.09 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH2:18]([N:21]([CH2:30][CH:31]=[CH2:32])[C:22]1([CH3:29])[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)[CH:19]=[CH2:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:28][CH:25]1[CH2:26][CH2:27][C:22]([N:21]([CH2:18][CH:19]=[CH2:20])[CH2:30][CH:31]=[CH2:32])([CH3:29])[CH2:23][CH2:24]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: C=CCN(CC=C)C1(C)CCC(N)CC1
Product: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 47.2 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (300 mg, 0.966 mmol) was reacted with N1,N1-diallyl-1-methylcyclohexane-1,4-diamine (400 mg, 1.93 mmol) to afford the desired product (220 mg, 47%) as a yellow solid: ESI MS m/z 482 [C26H32BrN3O+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:4].C([Li])CCC.CCCCCC.Cl.[C:26](=O)([O-])[O-:27].[K+].[K+]>O1CCCC1.CN(C)C=O>[CH:26]([C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ncccc1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
2,2-Dimethyl-N-pyridin-2-yl-propionamide (20.3 g) was dissolved in tetrahydrofuran (230 ml) to prepare a solution which was cooled to −78° C. A 2.44 M n-butyllithium/n-hexane solution (100 ml) was gradually added dropwise thereto, and the mixture was stirred at −78° C. for 15 min. The reaction solution was stirred at 0° C. for 2 hr and was then again cooled to −78° C. A solution of N,N-dimethylformamide (25.0 g) in tetrahydrofuran (25 ml) was gradually added dropwise thereto. The temperature of the reaction solution was raised to room temperature. The reaction solution was then poured into a mixture of ice (50 g) with 6 N hydrochloric acid (150 ml), and the mixture was stirred at room temperature for 20 min. The aqueous layer was neutralized with potassium carbonate powder and was extracted with diethyl ether, and the diethyl ether layer was then washed with water and saturated brine and was dried over magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give N-(3-formyl-pyridin-2-yl)-2,2-dimethyl-propionamide (11.8 g, yield 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.Cl[C:15]1[S:16][C:17]([C:26]#[N:27])=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1.N1C2=CC3COCOC=3C=C2N=C1>>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:9]([C:15]3[S:16][C:17]([C:26]#[N:27])=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: N#Cc1sc(Cl)nc1-c1ccccc1
Reactant: COc1cc2nc[nH]c2cc1OC
Agent: c1nc2cc3c(cc2[nH]1)COCO3
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C#N)s3)c2cc1OC
Yield: 47 %

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carbonitrile (48.8 mg, yield 47%) was prepared from 5,6-dimethoxybenzimidazole (76 mg, 0.43 mmol) and 2-chloro-4-phenyl-thiazole-5-carbonitrile as described in Example 1 (63 mg, 0.28 mmol). MS M/z 363 (M+1)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)C(Cl)=O)([O-])=O.[CH2:13]([O:20][C:21](=[O:25])[C@@H:22]([CH3:24])N)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Sn](Cl)(Cl)(Cl)Cl>>[CH2:13]([O:20][C:21](=[O:25])[C@@H:22]([C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=1)[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn](Cl)(Cl)Cl
Product: C[C@@H](C(=O)OCc1ccccc1)c1cccc(N)c1

Procedure:
3-Nitrobenzoyl chloride was reacted with D-alanine benzyl ester, then reduced with tin chloride to produce (R)-2-(3-amino-phenyl)-propionic acid benzyl ester. This was reacted with 5-(2-adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) according to the procedure of Example 20, step d. The benzyl ester was hydrogenolysed using the same procedure as in Example 1, step e to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 11.96 (1H, br s), 9.46 (1H, br s), 8.57 (1H, br d), 8.16 (1H, s), 7.96 (1H, d), 7.54 (1H, d), 7.40-7.35 (1H, m), 4.41 (1H, m), 2.87 (2H, m), 2.63 (1H, m), 1.94-1.32 (30H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.15; H, 8.33; N, 9.04%. C39H59N5O9.2.0 mols H2O requires: C, 60.21; H, 8.16; N, 9.00%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1c(C)cccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(CBr)cccc1OC
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a solution of ethyl 2-methoxy-6-methylbenzoate (0.813 g, 4.19 mmol) in CCl4 (8 mL) was added recrystallized N-bromosuccinimide (0.751 g, 4.22 mmol) followed by benzoyl peroxide (52 mg, 0.22 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (8:1 hexanes-EtOAc) provided 0.68 g (60%) of ethyl 6-(bromomethyl)-2-methoxybenzoate as a colorless oil. 1H NMR (CDCl3) δ 1.42 (t, 3H, J=7.2 Hz), 3.84 (s, 3H), 4.45 (q, 2H, J=7.2 Hz), 4.50 (s, 2H), 6.89 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=7.2 Hz), 7.34 (dd, 1H, J=7.2, 8.4 Hz).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH3:53][O:54][C:55](=[O:64])[C:56]1[CH:61]=[C:60]([CH:62]=O)[CH:59]=[N:58][CH:57]=1.C(O)(=O)C>C(#N)C.ClCCl>[CH3:53][O:54][C:55](=[O:64])[C:56]1[CH:61]=[C:60]([CH2:62][N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH:59]=[N:58][CH:57]=1
Reactant: COC(=O)c1cncc(C=O)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1cncc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)c1
Reaction time: 24 h
Yield: 89 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.100 g, 0.181 mmol), 5-formyl-nicotinic acid methyl ester (0.089 g, 0.543 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide (the title compound as an off-white foam (0.113 g, 90%). 1H NMR (CDCl3, 30 MHz) δ 1.21-1.43 (m, 1H), 1.61-1.71 (m, 1H), 2.04-2.13 (m, 2H), 2.32 (s, 3H), 2.71-2.83 (m, 1H), 3.10-3.18 (m, 1H), 3.89 (s, 3H), 4.14 (s, 3H), 4.32-4.50 (m, 2H), 4.83-5.10 (m, 2H), 5.64-5.0 (m, 1H), 6.89 (s, 1H), 7.21 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H), 8.35 (s, 1H), 8.83 (s, 1H), 9.12 (s, 1H); ESI MS m/z 702 [C31H28F9N7O2+H]+
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH:11]1([N:16]2[C:20]([NH2:21])=[C:19]([C:22]#[N:23])[C:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:17]2)[CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([N:16]2[C:20]([NH:21][C:8]([C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)=[O:9])=[C:19]([C:22]#[N:23])[C:18]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[N:17]2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(Cl)c1ccncc1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1N
Agent: Cl
Product: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)c1ccncc1
Temperature: 200 °C
Yield: 85.3 %

Procedure:
4-Pyridinecarboxylic acid chloride hydrochloride (4.3 g, 24 mmol), and 1-cyclopentyl-3-phenylmethyl-4-cyano-5-amino-1H-pyrazole (3.2 g, 12.0 mmol) were combined and heated to 200° C. under argon for 5 minutes. The reaction mixture was cooled to room temperature and the residue was partitioned between chloroform and sat. NaHCO3. The organic layer was separated, washed with additional sat. NaHCO3, dried over anhydrous MgSO4 passed through a plug of silica and the solvent was removed in vacuo to afford 3.8 g (84%) of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(4-pyridinecarboxamido)-1H-pyrazole as white crystals, m.p. 189°-191° C. when recrystallized from ethyl acetate and dried at 80° C. for 8 hours in high vacuum.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCCC[C@@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (528 mg) in 2-propanol (10 mL) were added 4-[(cis-2-hydroxycyclohexyl)amino]thiazol-2(5H)-one (500 mg) and piperidinium acetate (230 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (153 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH:12]1[CH2:17][NH:16][CH:15]([CH3:18])[CH2:14][NH:13]1.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][N:13]1[CH2:14][CH:15]([CH3:18])[NH:16][CH2:17][CH:12]1[CH3:11]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC1CNC(C)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1CN(Cc2ccc(Cl)c(Cl)c2)C(C)CN1

Procedure:
A solution of 1,2-dichloro-4-chloromethyl-benzene (1.1 ml 7.89 mmol) in DMF (5 ml) was added to 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) dissolved in DMF (25 ml). The reaction was stirred over night, poured into a mixture of EtOAc and sodium carbonate (5%). The water phase was washed twice with EtOAc and the combined organic phase once with brine, and dried over sodium sulfate. After evaporation the crude was dissolved in methanol. The dibensylated piperazine does not dissolve. The filtrate was filtered through a short silica column, using methanol as eluant and evaporated to give the pure product. Yield 812 mg, 38%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1Br.[Cl-].[CH3:13][Zn+]>C1COCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[O:5][C:6]=1[CH3:13]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Reactant: C[Zn+]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.7 %

Procedure:
Methyl 4,5-dibromo-2-furancarboxylate (3.7 g, 13.03 mmol) [prepared according to Example 127] and trans-dichlorobis(triphenylphosphine)Palladium (II) (0.46 g, 0.65 mmol) were combined in THF (50 ml) to give a yellow suspension. A THF solution of methylzinc chloride (11.40 ml, 22.81 mmol) was added dropwise at room temperature. After stirring at ambient temperature for 20 h, the solution was concentrated and purified using silica gel and eluting with 0-30% ethyl acetate/hexane to generate the title compound as a white solid (1.45 g, 6.61 mmol, 51% yield): LC-MS (ES) m/z 220 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=CC=C[CH:8]=2)[CH:3]=[CH:2]1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.C(OC(N1CCC[C@H]1CO)=O)(C)(C)C>>[Cl:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:8][C@@H:9]3[CH2:4][CH2:3][CH2:2][NH:1]3)=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Cl:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: Clc1ccc2[nH]c3c(OC[C@@H]4CCCN4)c4[nH]c5ccc(Cl)cc5c4cc3c2c1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is (S)-(+)-1-(tert-butoxycarbonyl)-2-pyrrolidinemethanol. 1H-NMR (400 MHz, CD3OD) δ ppm 8.46 (s, 1 H), 8.11 (d, J=2.4 Hz, 2 H), 7.41 (d, J=8.4 Hz, 2 H), 7.30 (dd, J=8.4, 2.4 Hz, 2 H), 4.33 (dd, J=10.0, 3.2 Hz, 1 H), 4.11 (dd, J=10.0, 8.4 Hz, 1 H), 3.91-3.82 (m, 1 H), 3.16 (t, J=7.2 Hz, 2 H), 2.16-2.05 (m, 1 H), 2.03-1.84 (m, 2 H), 1.72-1.62 (m, 1 H); MS (ESI) m/z 422.2 (M−H)−; MS (ESI) m/z 424.0 (M+H)+
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1.O1CCC[CH2:33]1.C[Mg]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4](=[O:30])[CH3:33])[CH2:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 10 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
N-Methoxy-N-methyl-2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide (0.20 g) was dissolved in absolute tetrahydrofuran (20 mL), and a 12% methylmagnesium bromide tetrahydrofuran solution (1.4 mL) was added under ice-cooling. The mixture was stirred at 10° C. for 5 hr under ice-cooling, acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=35:65-50:50), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (121 mg, yield: 67%) as colorless crystals.