Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:34])[NH:29]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:34])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(F)c1OC

Procedure:
In the same way as in Example 29, 210 mg (0.64 mmol) of (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 132 mg (0.97 mmol) of 5-aminoquinolin-2(1H)-one and 0.27 ml of titanium tetraethoxide are reacted to give 5-{[(2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 234 mg of crude imine are cyclized in the same way as in Example 29 at −20° C. with 2 ml (2 mmol) of 1 M boron tribromide solution to give the desired product. Preparative thin-layer chromatography on silica gel (hexane/2-propanol 17%) yields 15.4 mg of the desired product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](O)=[O:15].O.[OH-].[Na+]>C1COCC1>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][OH:15]
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1CO
Temperature: 80 °C
Yield: 19.9 %

Procedure:
To a stirred mixture of LiAlH4 (796 mg, 20.97 mmol) in anhydrous THF (20 mL) at rt was added portion-wise (1R,2R)-2-aminocyclohexanecarboxylic acid (1 g, 6.99 mmol). The mixture was heated at 80° C. for 4 h before it was cooled to 0° C. Water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. The mixture was filtered and the filtrate partitioned between a mixture of DCM, 1M aq NaOH, and saturated aq sodium potassium tartrate. The organic layer was separated and washed with 1M aq NaOH. The organic layer was separated, dried over MgSO4, filtered, and under reduced pressure to afford ((1R,2R)-2-aminocyclohexyl)methanol (180 mg) which was not purified further. LCMS (ESI) m/z 130 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][NH:33][C:34]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]1[CH:49]=[CH:48][C:47]([CH2:50]O)=[CH:46][CH:45]=1)=[O:35]>>[CH2:1]([O:8][C@H:9]([CH3:31])[CH2:10][NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:50][C:47]2[CH:46]=[CH:45][C:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[CH2:37][NH:36][C:34]([NH:33][CH3:32])=[O:35])=[CH:49][CH:48]=2)[C:18]1=[O:28])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Reactant: C[C@H](CNC(C)(C)CC(=O)N[C@@H]1CCc2ccccc2NC1=O)OCc1ccccc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@@H](C)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-[2(R)-benzyloxypropyl]amino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step C) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Example 48, Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CD3OD): δ 1.10 (s, 3H), 1.12 (s, 3H), 1.18 (d, 6 Hz, 3H), 1.95 (m, 1H), 2.12-2.39 (m, 3H), 2.40-2.63 (m, 3H), 2.63 (s, 3H), 3.70 (m, 1H), 4.13 (s, 2H), 4.42 (dd; 12, 8 Hz; 1H), 4.46 (d, 12 Hz, 1H), 4.59 (d, 12 Hz, 1H), 4.93 (d, 15 Hz, 1H), 5.23 (d, 15 Hz, 1H), 7.02-7.40 (m, 17H). FAB-MS: calculated for C41H49N5O4 675; found 676 (M+H, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[F:15][C:16]([F:21])([F:20])[C:17](=[O:19])[CH3:18].Cl>C1COCC1>[F:15][C:16]([F:21])([F:20])[C:17]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:19])[CH3:18]
Reactant: CC(=O)C(F)(F)F
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A solution of 1-bromo-4-methoxybenzene (19 ml, 150 mmol) in 300 ml of dry THF at −78° C. was treated with n-butyllithium (96 ml, 154 mmol) (1.6 M or 15% in hexanes, Strem). The resulting mixture was stirred for an additional 30 min. At −78° C., 1,1,1-trifluoropropan-2-one (16 ml, 180 mmol) was added and the mixture was stirred −78° C. and slowly warmed up overnight. The reaction mixture was treated with 100 ml of 5N HCl and concentrated. The layers were separated. The bottom layer (organic) was diluted with 50 ml of DCM, washed with 1×100 ml of H2O, and dried (MgSO4) and concentrated to give an oil which was purified by silica gel chromatography eluting with 0-5% EtOAc in hexanes to provide the title compound.
Reaction SMILES: OC1C=C(N2C3C=NC(OC)=CC=3N=C2)SC=1C(OC)=O.[OH:22][C:23]1[CH:27]=[C:26]([N:28]2[C:36]3[CH:35]=[C:34]([O:37][CH3:38])[N:33]=[CH:32][C:31]=3[N:30]=[CH:29]2)[S:25][C:24]=1[C:39]([O:41][CH3:42])=[O:40].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[C:57]([F:60])([F:59])[F:58]>CN(C)C=O>[CH3:38][O:37][C:34]1[N:33]=[CH:32][C:31]2[N:30]=[CH:29][N:28]([C:26]3[S:25][C:24]([C:39]([O:41][CH3:42])=[O:40])=[C:23]([O:22][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=4[C:57]([F:58])([F:59])[F:60])[CH:27]=3)[C:36]=2[CH:35]=1
Reactant: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1O
Reactant: FC(F)(F)c1ccccc1CBr
Agent: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnc(OC)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1.20 g of an isomeric mixture of methyl 3-hydroxy-5-(6-methoxy-3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and methyl 3-hydroxy-5-(6-methoxy-1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate (example C6) in 15 ml anhydrous N,N-dimethylformamide were added 0.65 g of K2CO3 and 1.12 g of 1-(bromomethyl)-2-(trifluoromethyl)benzene under a nitrogen atmosphere. The reaction mixture was stirred for 12 h at room temperature and poured into 400 ml of ice water. The resulting solid was filtered, washed with water and dried under vacuum to give the crude title compounds as an isomeric mixture. The isomeric mixture was used for the next steps (examples 16, 17 and 18) without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[N:11]=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(F)cc2)cn[nH]1
Product: Fc1ccc(-c2cnnc(Cl)c2)cc1
Temperature: 110 °C

Procedure:
5-(4-Fluorophenyl)pyridazin-3(2H)-one (2.15 g, 11.3 mmol) was dissolved in POCl3 (133 ml) and the mixture was refluxed at 110° C. for 30 min. The reaction was cooled in an ice bath and slowly quenched with aqueous sodium hydrogen carbonate (200 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 9.67 (d, 1H); 8.28 (d, 1H); 8.07 (dd, 2H); 7.42 (t, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21]C)[CH:19]=[CH:20][C:9]=3[C:8](=[O:23])[C:7]2=1.Cl.N1C=CC=CC=1>O>[OH:21][C:18]1[CH:19]=[CH:20][C:9]2[C:8](=[O:23])[C:7]3[C:6]4[C:14](=[CH:2][C:3]([C:24]#[N:25])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3c(Br)c(C#N)ccc3c1C2=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 160 °C
Reaction time: 28 h

Procedure:
4-Bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U5, 325 mg, 0.822 mmol) was added with pyridine hydrochloride salt (3.80 g, 32.89 mmol) and stirred at 160° C. for 28 hr. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried over sodium sulfate, and filtered. After concentration under reduced pressure, the title compound was obtained as a crude product.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[C:10]([OH:22])(=[O:21])[CH2:11][C:12]([CH2:17][C:18]([OH:20])=[O:19])([C:14]([OH:16])=[O:15])[OH:13].[Ca+2].[Ca]>>[C:10]([O-:22])(=[O:21])[CH2:11][C:12]([CH2:17][C:18]([O-:20])=[O:19])([C:14]([O-:16])=[O:15])[OH:13].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])CC(O)C(=O)[O-]
Agent: [Ca+2]
Agent: [Ca]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Japanese patent application Sho 56/097,248 (Tanaka, 1981) discloses a calcium citrate malate salt of increased solubility. This salt is a 5:2:2 ratio of calcium:citrate:malate, formed by mixing calcium carbonate with citric and malic acids in water at 50° C. to 60° C. and separating the white crystalline material from the mother liquor. When the product is dry (oven drying is used), the temperature is raised to 110° C. -120° C. to sterilize the powder.
Reaction SMILES: [CH3:1][O:2][P:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2.[I:21]I.[OH-].[K+]>CN(C)C=O>[CH3:1][O:2][P:3]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[I:21]
Reactant: COP(=O)(Oc1ccc2[nH]ncc2c1)c1ccccc1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COP(=O)(Oc1ccc2[nH]nc(I)c2c1)c1ccccc1
Yield: 71.1 %

Procedure:
Phenylphosphonic acid 3-iodo-1H-indazol-5-yl ester methyl ester is prepared according to procedure A using 76 mg of phenylphosphonic acid 1H-indazol-5-yl ester methyl ester, 134 mg of iodine and 30.6 mg of potassium hydroxide ground before hand in 3 ml of dimethylformamide. The crude is purified by flash chromatography on silica with a particle size of 15-35 μm. Eluent: ethyl acetate/cyclohexane 1:1 to obtain 77.6 mg of phenyl-phosphonic acid 3-iodo-1H-indazol-5-yl ester methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=O)[O:19]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.C(N(CC)CC)C.Cl.[F:35][CH2:36][CH2:37][NH2:38]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]([NH:38][CH2:37][CH2:36][F:35])=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]1
Reactant: CC1(C)OB(c2ccc(NC(=O)Oc3ccccc3)cc2F)OC1(C)C
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirring solution of phenyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (intermediate 30) (1.6 g, 4.48 mmol) in dry DMF was added triethylamine (2.03 mL, 14.55 mmol) and 2-fluoroethanamine hydrochloride (2.23 g, 22.40 mmol). The mixture was stirred at 50° C. for 2 h. The solvent was then removed in vacuo affording the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>CCOC(C)=O.O.CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([F:9])=[C:4]([F:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Br)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1cc(Br)cc(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
A solution of DMF (100 mL), 5-bromo-2,3-difluorophenol (10 g, 47.85 mol), and K2CO3 (7.27 g, 52.63 mol) and benzyl bromide (9 g, 52.63 mol) were combined at 0° C. under N2. The solution was allowed to warm to rt and stirred overnight. H2O, Et3N (2 eq) and EtOAc (5000 mL) were added and the organic layer separated. The aqueous layer was washed with EtOAc (2×) and the combined organic fractions were washed with 1M HCl (2×), sat. aq. NaHCO3 (2×), dried, and concentrated. The crude product was purified by Biotage (gradient 100% hexanes-60% EtOAc/hexanes) to afford 10.08 g of product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[C:10]2[C:15](=[O:16])[C:14](=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:13][S:12](=[O:27])(=[O:26])[CH2:11]2)=[CH:5][CH:4]=1.[NH2:28][C:29]1[S:30][CH2:31][CH2:32][N:33]=1>CCC(C)=O>[S:30]1[CH2:31][CH2:32][N:33]=[C:29]1[NH:28][C:15]1([OH:16])[C:10](=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][S:12](=[O:26])(=[O:27])[CH2:13][C:14]1=[CH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: NC1=NCCS1
Reactant: COc1ccc(C=C2CS(=O)(=O)CC(=Cc3ccc(OC)cc3)C2=O)cc1
Solvent: CCC(C)=O
Product: COc1ccc(C=C2CS(=O)(=O)CC(=Cc3ccc(OC)cc3)C2(O)NC2=NCCS2)cc1
Yield: 102.8 %

Procedure:
A stirred solution of tetrahydro-3,5-bis(4-methoxyphenylmethylene)-4H-thiopyran-4-one-1,1-dioxide (5.7 g, 0.014 mole) in 100 ml of MEK is treated with 2-amino-2-thiazoline (2.1 g, 0.020 mole). After heating at reflux for 1 hour the yellow mixture becomes colorless. After cooling for several hours, the product is filtered and washed with MEK and ether to give 7.0 g (97%) of colorless product, m.p. 194°-196°.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH2:10]2)=O)C.Br.[OH-].[Na+]>C(O)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:9]2[CH2:8][CH:7]3[NH:6][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)N1C2CCC1CC(Cc1ccc(Cl)cc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Clc1ccc(CC2CC3CCC(C2)N3)cc1

Procedure:
A mixture of 2 g of 3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester, 20 mL of 48% HBr and 5 mL of acetic acid was heated to reflux for 2 h. After cooling in an ice bath, the solution was basified to pH 10 by addition of NaOH pellets, extracted with 3×100 mL of chloroform, and the combined extracts dried over MgSO4. Removal of solvents under reduced pressure gave 1.5 g of 2:1 exo:endo 3-(4-chloro-benzyl)-8-aza-bicyclo[3.2.1]octane as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][CH2:13][CH3:14])=[N:6][C:5]=2[S:4][N:3]=1.[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[CH2:21]([N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[N:6]=[C:7]1[CH2:12][CH2:13][CH3:14])[C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1
Reactant: CCCc1nc2snc(C)c2c(=O)[nH]1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Yield: 41 %

Procedure:
To a solution of 30 (730 mg, 3.5 mmol) in dioxane (10 mL) was added BnBr (830 μl, 7 mmol) and Cs2CO3 (1.6 g, 4.9 mmol). The reaction mixture was stirred at room temperature over night, then diluted with EtOAc, washed with water, dried and purified by silica gel column chromatography to give 31 (430 mg, 42%). 1H-NMR (400 MHz, CDCl3): δ 7.15–7.40 (m, 5H), 5.40 (s, 2H), 2.84 (s, 3H), 2.75 (t, J=7.61 Hz, 2H), 1.80 (m, 2H), 0.99 (t, J=7.38 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[C:28]([F:29])=[CH:27][C:26]([F:30])=[CH:25][C:24]=1[CH2:31][C:32](=[O:34])[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CS(C)=O.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH:31]([C:24]1[CH:25]=[C:26]([F:30])[CH:27]=[C:28]([F:29])[C:23]=1[F:22])[C:32](=[O:34])[CH3:33])[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cc1cc(F)cc(F)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1cc(F)cc(F)c1F
Reaction time: 30 h
Yield: 59.7 %

Procedure:
To a solution of 2 (10.98 g, 33.7 mmol) in THF (50 mL) was added TEA (4.8 g, 47.4 mmol) in portions at 15-20° C. The mixture was stirred for 30 h. After the reaction was complete, the solution was concentrated to give crude 7. To a solution of 44 (6.3 g, 33.7 mmol) and Cs2CO3 (5.0 g, 15.3 mmol) in DMSO (35 mL) was added slowly crude 7 in DMSO (35 mL) over 30 min at 15-20° C. The mixture was stirred for 1 h. After the reaction was complete, the mixture was partitioned with water and MTBE (50 mL) and extracted twice by MTBE. The combined organic layer was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to 45 (8.4 g, 60% yield). 1H NMR (DMSO-d6, 400 MHz): δ 6.77 (d, 1H), 6.59 (d, 1H), 5.11 (m, 1H), 4.93-4.89 (m, 1H), 4.12 (s, 2H), 2.66 (d, 1H), 2.05-2.01 (d, 3H), 1.38 (m, 9H), 1.18-1.15 (m, 6H); MS (ESI) m/e [M+H]+: 418.18.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Reactant: C1CNCCN1
Product: O=C(N1CCNCC1)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Yield: 19 %

Procedure:
The title compound (351 mg, 19%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and piperazine similarly to the procedure used for example 149. LRMS APCI+ m/z 400 [MH]+.
Reaction SMILES: C([O:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=O)C>CO.N.C(OCC)C.CCCCCC>[OH:4][C@H:5]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(=O)O[C@H](CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: N
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@H](O)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 16 h
Yield: 86.2 %

Procedure:
8.0 g of tert.butyl 2(R)-acetoxy-4-(4-nitrophenyl)butanoate were dissolved in 200 ml of methanol saturated with ammonia at 0° C. and the mixture was stirred for 16 hours. Evaporation of the mixture in vacuo gave 7 g of an almost colorless oil which was dissolved in an equal volume of diethyl ether/n-hexane (1:1) and eluted through a silica gel column with the same solvent mixture to give 6 g of tert.butyl 2(R)-hydroxy-4-(4-nitrophenyl)butanoate as a colorless crystalline solid having a melting point of 41°-42° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]#[N:12])[N:7]([CH3:13])[C:6](=[O:14])[CH2:5]2.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17](B(O)O)[CH:16]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)=[C:10]([C:11]#[N:12])[CH:9]=2)[CH2:5][C:6]1=[O:14]
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)Cc2cc(Br)c(C#N)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2cc(-c3cccnc3)c(C#N)cc21
Temperature: 100 °C

Procedure:
To 5-bromo-1-methyl-2-oxo-2,3-dihydro-1H-indole-6-carbonitrile (58 mg, 0.23 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 28 mg, 0.23 mmol), 1,2-dimethoxyethane (2.0 mL) and 2 M aqueous sodium carbonate (0.230 mL, 0.46 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (105 mg, 0.009 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 1.75 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-2-oxo-5-pyridin-3-yl-2,3-dihydro-1H-indole-6-carbonitrile; HRMS: (ESI) m/z 248.0838 (M−H)−; 1H NMR (400 MHz, CDCl3) δ ppm 3.30 (s, 2H), 3.68 (s, 2H), 7.19 (s, 1H), 7.42 (s, 1H), 7.49-7.58 (m, 1H), 8.02 (d, J=7.6 Hz, 1H), 8.72 (dd, J=4.8, 1.1 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([NH2:17])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:7]=1.Cl.CN(C)CCC([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O.O>CN(C=O)C>[C:25]1([C:3]2[CH2:2][CH2:7][N:6]3[N:8]=[C:9]([NH2:17])[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[C:5]3[N:4]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nn2c(c1-c1ccccn1)N=C(c1ccccc1)CC2
Temperature: 160 °C
Yield: 90.7 %

Procedure:
6-Bromo-3-pyridin-2-yl-pyrazolo[1,5-a]pyrimidin-2-ylamine (0.52 g, 3.01 mmol) and 3-dimethylamino-1-phenyl-propan-1-one hydrochloride (0.64 g, 3.01 mmol) were suspended in dry DMF (10 mL). The mixture was heated at 160° C. for 3 hours with stirring. After allowing the reaction to cool down to room temperature, the mixture was poured into cold water. The resulting precipitate was filtered and dried to afford the title compound as a yellow solid (0.79 g, 93% yield). MS (ES+) 290. δH (DMSO-d6) 3.3 (2H, m), 4.1 (2H, m), 6.1 (2H, s), 7.2 (1H, m), 7.7 (4H, m), 7.9 (1H, t), 8.2 (1H, m), 8.4 (1H, d), 8.6 (1H, d).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:25]#[N:26])(C)C>[I-].[Zn+2].[I-].CCOCC>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([C:25]#[N:26])=[CH:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: N#CC1=CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reaction time: 15 h
Yield: 44 %

Procedure:
6-Benzenesulfonyl-3,4-dihydro-2H-naphthalen-1-one from Preparation 1 above (4.0 g, 14 mmol), trimethylsilyl cyanide (10.0 g, 100 mmol) and Zinc Iodide (0.25 g) were combined and stirred under nitrogen for 15 hours. The reaction mixture was then diluted by addition of 200 mL of Et2O, washed with cold water, and the organic layer was dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in 250 mL of toluene, and 0.5 g of paratoluene sulfonic acid was added. The reaction mixture was refluxed for three hours, cooled, and the the solvent was removed under reduced pressure. The crude product was eluted through silica under medium pressure with 5% EtOAc in hexanes to yield 1.8 g (6.1 mmol, 44%) of (racemic) 6-benzenesulfonyl-3,4-dihydro-naphthalene-1-carbonitrile as an oil. MS: 296 (M+H)+.