Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[OH:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[O:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: COc1ccc2oc(=O)cc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2oc(=O)cc(Oc3c(Cl)cccc3Cl)c2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A stirred mixture of 4-chloro-6-methoxycoumarin (1.0 g, 4.75 mmole), 2,6-dichlorophenol (0.85 g, 5.22 mmole) and K2CO3 (0.98 g, 7.12 mmole) in acetonitrile, under N2, is heated at reflux temperature for 16 hours, cooled to room temperature and poured into ice water. This mixture is extracted several times with ether. The extracts are combined and concentrated in vacuo to give a tan solid residue. The residue is crystallized from ethyl acetate/hexane to afford the title product as tan crystals, 1.17 g (73% yield), mp 170°-171° C., identified by IR, 1HNMR, 13CNMR, and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].ClC1C=CC(S[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=2)=[O:30])=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29](=[O:30])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[N:32]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=C(Sc1ccc(Cl)cc1)c1cccc(C(F)(F)F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC(C(=O)c1cccc(C(F)(F)F)n1)c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of 4-fluorophenylacetonitrile (0.12 mL, 1.0 mmol) in dry tetrahydrofuran (2 mL) is treated dropwise with potassium bis(trimethylsilyl)amide (0.5 M toluene, 3.0 mL, 1.5 mmol) at 0° C. under an atmosphere of nitrogen. The mixture is stirred 10 min then 6-trifluoromethyl-pyridine-2-carbothioic acid S-(4-chloro-phenyl) ester is added all at once. The mixture is allowed to warn to room temperature then warmed to reflux for 10 min, at which time the reaction is complete by TLC (methylene chloride). The mixture is allowed to cool then poured into 10% citric acid and extracted into methylene chloride. The methylene chloride solution is dried over magnesium sulfate and concentrated in vacuo. The residue is purified on a silica gel cartridge prepared with hexane then eluted with methylene chloride to yield 204 mg (66%) 2-(4-fluoro-phenyl)-3-oxo-3-(6-trifluoromethyl-pyridin-2-yl)-propionitrile. MS ES− m/z 307 (M−1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1.C(=O)(O)[O-].[Na+].[C:23]([C:25]1[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:27]2[CH2:34][CH2:33][CH2:32][C:28]2=[N:29][C:30]=1[S-:31])#[N:24].[Na+]>O>[C:23]([C:25]1[C:26]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:27]2[CH2:34][CH2:33][CH2:32][C:28]2=[N:29][C:30]=1[S:31][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[S:6][CH:7]=1)#[N:24]
Reactant: COC(=O)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: N#Cc1c([S-])nc2c(c1-c1ccccc1)CCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CSc3nc4c(c(-c5ccccc5)c3C#N)CCC4)cs2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
315 mg (1.18 mmol) of methyl 4-[4-(chloromethyl)-1,3-thiazol-2-yl]benzoate (prepared as described in WO 2005/011685) and 329 mg (3.92 mmol) of sodium bicarbonate are added to the reaction mixture from Example 18A, and the mixture is stirred at RT for 16 h. 50 ml of water were added, and the reaction was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5, 15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6](B(O)O)[CH:7]=1.FC(F)(F)S(O[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O.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>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Cl)ccc2C(F)(F)F)CC1
Temperature: 80 °C
Yield: 84 %

Procedure:
A mixture of (5-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1.5 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes) to give tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.614 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.5 Hz, 1H), 7.37-7.22 (m, 1H), 7.22 (d, J=1.68 Hz, 1H), 5.60 (br, 1H), 4.02 (br, 2H), 3.61 (br, 2H), 2.34 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C@@H:26]([OH:45])[CH2:27][NH:28][C:29]([CH3:44])([CH3:43])[CH2:30][CH2:31][N:32]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:34]=[CH:33]2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:19]([O:18][C:17]1[CH:16]=[CH:15][C:14]([C@@H:26]([OH:45])[CH2:27][NH:28][C:29]([CH3:44])([CH3:43])[CH2:30][CH2:31][N:32]2[CH:36]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:34]=[CH:33]2)=[CH:13][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Product: CC(C)(CCn1cnc(-c2ccccc2)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.7 %

Procedure:
0.10 mL (41 mmol) benzenesulphonic acid chloride were slowly added to a solution of 0.20 g (41 mmol) (R)-1-(3-amino-4-benzyloxyphenyl)-2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-ethanol in 5 mL pyridine at 0° C. with vigorous stirring. After the addition was complete the reaction mixture was stirred for 4 h at 0° C. and then poured into 40 mL ice water/ethyl acetate (1:1). The phases were separated and the aqueous phase was extracted three times with 20 mL ethyl acetate. The combined organic phases were dried over magnesium sulphate and the solvent was removed using the rotary evaporator. 0.14 g (0.28 mmol, 99%) (R)—N-(2-benzyloxy-5-{2-[1,1-dimethyl-3-(4-phenylimidazol-1-yl)-propylamino]-1-hydroxyethyl}-phenyl)-benzenesulphonamide was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:24]S(C3C=CC(C)=CC=3)(=O)=O)([CH2:13]S(C3C=CC(C)=CC=3)(=O)=O)[CH2:10][C:9]=2[C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][CH:3]=1.[I-].[Na+]>CN(C=O)C.[Zn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C:11]3([CH2:10][C:9]=2[C:35]2[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:42])=[O:43])=[CH:39][CH:40]=2)[CH2:24][CH2:13]3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(c3ccc(F)cc3)=C(c3ccc(S(C)(=O)=O)cc3)C2)cc1
Agent: [I-]
Agent: [Na+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
Under nitrogen, a solution of 1.02 g (1.49 mmol) of 1-[2-(4-fluorophenyl)-4,4-di(tosylmethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 10) in 24 mL of DMF was treated with 3.23 g (21.55 mmol) of sodium iodide and 1.61 g (24.63 mmol) of zinc dust. The reaction was stirred at 150° C. for 1.5 hours, concentrated in vacuo, and partitioned between water and ethyl acetate. The organic phase was washed with sodium sulfite, water, brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel to give 437 mg (86%) of 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene as a colorless solid: mp 140.5°-142.0° C.; NMR (CDCl3) δ 0.69 (s, 4H), 2.92 (s, 4H), 3.04 (s, 3H), 6.93 (t, J=9 Hz, 2H), 7.10 (dd, J=5 and 9 Hz, 2H), 7.32 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H). HRMS. Calc'd for C20H19FO2S: 342.1090. Found: 342.1126. Anal. Calc'd for C20H19FO2S: C, 70.15; H, 5.59; F, 5.55; S, 9.36. Found: C, 70.10; H, 5.69; F, 5.50; S, 9.60.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:17])[C:4]([O:6][CH:7]1[CH2:15][CH:14]2[CH2:16][CH:8]1[CH:9]1[CH:13]2[CH2:12][CH2:11][CH2:10]1)=[O:5].N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][CH2:2][C:3](=[CH2:17])[C:4]([O:6][CH:7]1[CH2:15][CH:14]2[CH2:16][CH:8]1[CH:9]1[CH:13]2[CH2:12][CH2:11][CH2:10]1)=[O:5])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(CO)C(=O)OC1CC2CC1C1CCCC21
Solvent: O
Solvent: c1ccncc1
Product: C=C(COC(C)=O)C(=O)OC1CC2CC1C1CCCC21
Reaction time: 20 h
Yield: 85.3 %

Procedure:
To a mixture of 23.6 g of 8-tricyclo[5.2.1.02,6]decyl α-(hydroxymethyl)acrylate and 15.8 g of pyridine was added 15.3 g of acetic anhydride. The mixture was stirred for 20 hours. Water was added to the reaction solution to stop the reaction, followed by conventional aqueous workup. The solvent was distilled off in vacuo. Purification by distillation (boiling point 123° C./13 Pa) gave 23.7 g (yield 90%) of 8-tricyclo[5.2.1.02,6]decyl α-(acetoxymethyl)acrylate represented by formula (12).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH3:15])[C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:16])[N:3]=1.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[Cl:16][C:4]1[N:3]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:1]=[C:2]2[CH:14]=[C:13]([CH3:15])[C:5]=1[C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7]
Reactant: Cc1cc(N)nc(Cl)c1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2c(Cl)c(C(=O)OC(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of tert-butyl 6-amino-2-chloro-4-methylnicotinate (9.4 g, 38.7 mmol, 1 equiv) and ethyl bromopyruvate (6.5 mL, 46.5 mmol, 1.2 equiv) in EtOH (194 mL) was heated to reflux for 2 h. Upon cooling to ambient temperature, the solution was concentrated in vacuo. The residue was triturated in ether and filtered to provide the product (11.4 g, 70%) as a cream colored solid. LCMS (ESI, M+1): 339.1.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:47]([NH2:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:47]([NH:54][C:21]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][C:12]([C:10]([N:7]1[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]1)=[O:11])=[CH:20][CH:19]=2)=[O:23])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCc1ccccc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCc4ccccc4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), benzylamine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[NH2:5][C:6]1[CH:13]=[C:12](F)[C:9]([C:10]#[N:11])=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[NH2:5][C:6]1[CH:13]=[C:12]([NH:4][CH:1]([CH3:3])[CH3:2])[C:9]([C:10]#[N:11])=[CH:8][N:7]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CC(C)N
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(N)ncc1C#N
Temperature: 50 °C

Procedure:
A mixture of isopropylamine (1.83 ml, 21.3 mmol), 6-amino-4-fluoronicotinonitrile (intermediate 21, 972 mg, 7.09 mmol) and diisopropylethylamine (3.71 ml, 21.3 mmol) in DMA (17 ml) was heated at 50° C. in a septum sealed reaction vessel for 48 h. The reaction mixture was then cooled, evaporated and purified by normal phase chromatography using an 40 g RediSep® column, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated. The residue was partitioned between DCM and 10% aqueous citric acid solution, the aqueous layer washed 2× with DCM, basified with NaHCO3, extracted with DCM (4×), the combined organic extracts from the basic extraction dried over Na2SO4 and evaporated to give the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 6.31 (s, br, 2H), 5.71 (d, br, 1H), 5.58 (s, 1H), 3.61-3.49 (m, 1H), 1.14 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CNC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(methoxycarbonylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde (0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.40 (9H, s), 1.80 (1H, m), 2.10 (1H, m), 3.00-3.80 (7H, m), 4.70 (1H, br, s), 7.20 (4H, m). ESI-MS m/z: 383(M+1), UV retention time: 2.91 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:29]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[CH:29]1([NH:34][CH:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:28][CH2:27][C:5]2=3)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCCC1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(NC2CCCC2)c2ccncc2)CCN(C)C1
Temperature: 100 °C

Procedure:
Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (240 mg, 0.60 mmol) was dissolved in 10 mL of 70% cyclopentylamine solution in water and heated at 100° C. for 18 h. The reaction mixture was cooled to RT and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 11 mg of cyclopentyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine. 1H NMR (CDCl3, freebase): δ (ppm): 8.51 (d, 2H), 7.17 (m, 4H), 7.003 (d, 1H), 4.16 (m, 2H), 4.05 (dd, 1H), 3.79 (dd, 2H), 2.9 (m, 1H), 2.83 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.39 (m, 1H), 1.99 (s, 2H), 1.7 (m, 2H), 1.5 (m, 2H), 1.4 (m, 1H), 1.9 (m, 2H). Chiral HPLC separates the racemate into enantiomers II-9a-b.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:10][C:11](=[O:41])[C:12]([NH:37][C:38](=[O:40])[CH3:39])([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=2)[C:19]1=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:8]([O:10][C:11](=[O:41])[C:12]([NH:37][C:38](=[O:40])[CH3:39])([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:24]=2)[CH2:19]1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]
Reactant: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(c1)CCC(C(NC(C)=O)(C(=O)OCC)C(=O)OCC)C2
Temperature: 0 °C
Reaction time: 12 h
Yield: 65.3 %

Procedure:
To a solution of triethylsilane (1.3 ml, 8.2 mmol) in 5 ml of CH2Cl2 was added compound 5 (1 g, 2.1 mmol) in 5 ml of CH2Cl2. The reaction mixture was stirred at room temperature under Ar and TiCl4 (0.09 ml, 8.2 mmol) was added dropwise. The resulting solution was stirred for 12 hours, cooled to 0° C. and quenched by slow addition of 10 ml of saturated NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with brine (2×30 mL) and dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, 20% EtOAc in hexanes) to provide 630 mg of compound 6 (65%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[S:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-diphenylthiazole as the raw materials, the same operation as the example 195(3) gave the title compound. (2-Amino-4,5-diphenylthiazole: refer to Nihon Kagaku Zasshi, 1962, 33, 209.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:13]([OH:17])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)O
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CC(=O)OC(C)(C)C)c1

Procedure:
To a solution of (3-methoxyphenyl)acetylchloride (25 g, 135 mmol), in dry dichloromethane (50 ml) was added t-butanol (14 ml) slowly with stirring. After stirring at room temperature for 5 minutes, the reaction was cooled in ice, and triethylamine (20 ml) added dropwise. After stirring a further 2 hours at room temperature, the reaction was poured into saturated aqueous sodium carbonate solution, extracted with dichloromethane, dried (MgSO4), solvents evaporated, and the residue chromatographed on silica (eluted 10% diethyl ether-petroleum ether bp 60°-80°), to give t-butyl (3-methoxyphenyl)acetate. 1H NMR (250 MHz, CDCl3) δ1.38 (9H, s), 3.42 (2H, s), 3.73 (3H, s), 6.69-6.82 (3H, m), 7.17 (1H, t, J=8.4Hz).
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]Cl)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41]>C(O)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41].[C:21]1([N:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][N:9]3[C:8](=[O:13])[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:11][C:10]3=[O:12])[CH2:31][CH2:32]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na]
Solvent: CCO
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CCCN1CCN(c2ccccc2)CC1
Reaction time: 16 h

Procedure:
5,5-diphenylhydantoin, 25.2 g (0.1 mole), was added to a solution of 2.3 g (0.1 mole) of sodium in 300 ml of anhydrous ethanol and the suspension was heated under reflux for half an hour. 4-phenyl-1-(3-chloropropyl)piperazine, (23.9 g, 0.1 mole) slowly was added to the suspension and the mixture was heated under reflux with stirring for 16 hours. The solvent was removed in vacuo, the concentrate was suspended in water, and the free base was extracted with chloroform. The dried extracts were concentrated in vacuo to an oil. The oil was dissolved in hot methanol and 14 g (0.12 mole) of maleic acid was added. The hot solution was filtered and the filtrate was cooled. The resulting solid was collected and recrystallized from an aqueous-methanol solution.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC(C)(C=O)N1CCCCC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCCC1
Temperature: 160 °C
Yield: 17.5 %

Procedure:
To a microwave vial was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (139.3 mg, 0.30 mmol), piperidine (0.04 mL, 0.35 mmol), 2-methyl-2-(1-piperidyl)propanal (68.8 mg, 0.4400 mmol) and toluene (3 mL). The vial was heated under microwave conditions at 160° C. for 3 hrs. The reaction was cooled and concentrated, then dissolved in ethyl acetate (30 mL) and washed with 2M HCl. The aqueous layer was basified to pH˜7.5 with sat. NaHCO3 and washed with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated and the crude material was purified by Isolera (1%-10% MeOH/ethyl acetate) to obtain 32 mg (18%) of the title compound. MS (pos. ion) m/z: 609 (M+1).