Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]1[CH2:22][N:21]([S:28]([CH2:31][CH:32]([CH:36]([CH3:38])[CH3:37])[C:33]([OH:35])=O)(=[O:30])=[O:29])[CH2:20][CH2:19][C:18]2=1.[Si]([O:46][NH2:47])(C(C)(C)C)(C)C.O>ClCCl>[OH:46][NH:47][C:33](=[O:35])[CH:32]([CH2:31][S:28]([N:21]1[CH2:20][CH2:19][C:18]2[C:17]3[C:25](=[CH:26][CH:27]=[C:15]([O:14][CH3:13])[CH:16]=3)[NH:24][C:23]=2[CH2:22]1)(=[O:29])=[O:30])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)O)C(C)C)C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc2[nH]c3c(c2c1)CCN(S(=O)(=O)CC(C(=O)NO)C(C)C)C3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.7 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (104 mg) was added to a slurry of 2-(6-methoxy-1,3,4,9-tetrahydro-β-carboline-2-sulfonylmethyl)-3-methylbutyric acid (172 mg) in dichloromethane (10 ml). The mixture was stirred for 5 minutes before addition of O-(t-butyldimethylsilyl)hydroxylamine (80 mg), then for 1.5 h. The mixture was poured into water (10 ml) and extracted with dichloromethane (3×15 ml). The combined organics were washed with water (2×50 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in dichloromethane (10 ml) and 1.0N hydrogen chloride in ether (2.5 ml) was added. The mixture was stirred at room temperature for 2 h. It was evaporated under reduced pressure and the residue chromatographed (SiO2, 5% methanol in dichloromethane) to give the title compound (37 mg, 21%) as a pale orange solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]2=[O:27])=[CH:19][CH:18]=1.B(C#N)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CO>[Si:1]([O:8][CH2:9][CH2:10][NH:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[NH:23][C:24]2=[O:27])=[CH:19][CH:18]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: N#CB([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
(tert-Butyldimethylsilanyloxy)acetaldehyde (93.9 μL, 0.493 mmol) and acetic acid (169 μL, 2.96 mmol) were added to a methanol solution (30 ml) that contained the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (150 mg, 0.493 mmol) prepared in step C of Example 1-1. The obtained solution was cooled to 0° C., and sodium cyanoborate (1M THF solution, 1.48 mL, 1.48 mmol) was then added thereto. The obtained mixture was stirred at a room temperature for 18 hours. The reaction solution was poured into a mixed solution of ethyl acetate and a saturated sodium bicarbonate aqueous solution. An organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1), so as to obtain 7-[2-(tert-butyldimethylsilanyloxy)ethylamino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (210 mg, 92%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[CH2:8][NH:9][CH3:10].[C:11]([O:15][C:16]([NH:18][S:19](N1C=CC(=[N+](C)C)C=C1)(=[O:21])=[O:20])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][O:5][CH2:4][C@H:3]1[CH2:8][N:9]([CH3:10])[S:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])(=[O:20])=[O:21]
Reactant: CNCC1COCCO1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1-(1,4-dioxan-2-yl)-N-methylmethanamine hydrochloride (0.760 g, 4.55 mmol), N-[1-{[(tert-butoxycarbonyl)amino]sulfonyl}pyridin-4(1H)-ylidene]-N-methylmethanaminium (1.51 g, 5.00 mmol), and triethylamine (1.55 mL, 11.4 mmol) were slurried in 50 mL dichloromethane and stirred at ambient temperature. After 12 hours, the solution was concentrated in vacuo and purified by silica chromatography (50-100% ethyl acetate/hexanes gradient) to afford the title compound. LRMS (APCI) calc'd for (C11H22N2O6SNa) [M+Na]+, 333.1; found, 333.1.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[S:41]([NH2:44])(=[O:43])=[O:42]>>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:24])(=[O:42])=[O:43]
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cc3ccccc3s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J.; Leu, Y.; et al. J. Med. Chem., 1997, 40, 2276; Graham, S. L.; Shepard, K. L.; et al. J. Med. Chem., 1989, 32, 2548).
Reaction SMILES: CCCCC[C@H](O)CC[C@H]1[C@H]([OH:22])C[C@H]2[C@@H]1CC1C(C2)=C(OCC(O)=O)C=CC=1.[NH+]1C=CC=CC=1.C(CCOP([O-])([O-])=O)#N.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>N1C=CC=CC=1.O>[C:51]([NH:50][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)([NH:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:22]
Reactant: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N#CCCOP(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The procedure was adapted after Steroids, 2(6), 567-603 (1963). The methyl ester of treprostinil (2) (60 mg, 0.15 mmoles) was dissolved in 2 ml dry pyridine and a pyridinium solution of the previously prepared pyridinium solution of 2-cyanoethylphosphate 1M (0.3 ml, 0.3 mmoles) (cf. Methods in Enzymology, 1971, 18(c), 54-57) were concentrated to dryness in vacuo at 40° C. Anhydrous pyridine was added and the reaction mixture was again concentrated; the operation was repeated twice in order to remove water completely. Finally the residue was dissolved in 2 ml anhydrous pyridine and 190 mg (0.9 mmoles) dicyclohexylcarbodiimide were added as a solution in 2 ml anhydrous pyridine. The reaction mixture in a closed flask was stirred magnetically for 48 hours at room temperature. 1 ml water was added and after one hour, the mixture was concentrated to a thick paste in vacuo. The reaction mixture was treated overnight at room temperature with 3 ml of a 1/9 water/methanol solution containing 35 mg sodium hydroxide. The white solid (dicyclohexylurea) formed was removed by filtration and it was washed well with water. The aqueous-methanolic solution was concentrated almost to dryness in vacuo, water was added and the solution was extracted with n-butanol (3×2 ml), then with methylene chloride (1×2 ml). The pH of the solution was adjusted to 9.0 by treatment with a sulfonic acid ion exchange resin (H+ cycle-Dowex), treatment with Dowex resin for a longer time (˜12 hours) lead to both the cleavage of the TBDMS group and the recovery of the free carboxyl group. The resin was filtered and the solution was concentrated to dryness affording the corresponding bisphosphate 4 (43 mg, yield 52%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C(C1C=CC=CC=1)(=O)C.P(Cl)(Cl)(Cl)(Cl)Cl.[F:35][CH:36]([F:45])[O:37][C:38]1[CH:43]=[CH:42][C:41](I)=[CH:40][CH:39]=1.Cl>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.[Cu]I.C(N(CC)CC)C>[F:35][CH:36]([F:45])[O:37][C:38]1[CH:43]=[CH:42][C:41]([C:19]#[C:18][C:15]2[CH:14]=[CH:13][C:12]([C@H:9]3[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]3)=[CH:17][CH:16]=2)=[CH:40][CH:39]=1
Reactant: C#Cc1ccc([C@H]2CC[C@H](CCCCC)CC2)cc1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC(=O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](c2ccc(C#Cc3ccc(OC(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 15.3 g of 4-(trans-4-pentylcyclohexyl)phenylacetylene (available from the acetophenone by dehydration, using PCl5 /KOT), 16.2 g of difluoromethoxy-4-iodobenzene, 100 ml of triethylamine, 0.085 g of bis(triphenylphosphine)dichloropalladium and 0.11 g of copper(I) iodide is stirred at room temperature for 3 hours. The cloudy mixture is stirred into dilute hydrochloric acid (500 ml of water+200 ml of 37% hydrochloric acid), extracted with t-butyl methyl ether and worked up as usual. m.p.: 62° C., c.p.: 203.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][Si](C)(C)C)=[C:4]([CH3:6])[CH3:5].F[B-](F)(F)F.[C:17]1([N+:23]#[N:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(OCC)C>[CH3:5][C:4]([N:24]=[N:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:6])[C:3]([O:2][CH3:1])=[O:7]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: N#[N+]c1ccccc1
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)C(C)(C)N=Nc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
1.0 mmol of (1-methoxy-2,2-dimethylethenyl)oxytrimethylsilane was placed in a 20-ml flask, followed by the addition of 3 ml of pyridine as a solvent. 1.3 mmol of benzenediazonium tetrafluoroborate was added to the flask. The obtained mixture was stirred at 0° C. in a nitrogen atmoshere for 2 hours. The reaction mixture was diluted with diethyl ether and washed with 1.5N hydrochloric acid, water and a saturated aqueous solution of common salt successively. The obtained organic phase was dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The obtained oily mixture was subjected to silica gel thin-layer chromatography to obtain 0.90 mmol of methyl 2-methyl-2-phenylazopropionate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19](/[CH:24]=[C:25](/[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])\[C:26]#[N:27])[CH:20]=[C:21]([F:23])[CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:24]([C:19]2[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([Cl:16])[CH:18]=2)[C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[F:35])([C:26]#[N:27])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cc(F)cc(Cl)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 28.7 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-5-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2.5 g, 8 mmol) prepared in Example 83a, AgF (1.0 g, 8 mmol), and triethylamine (2.8 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-5-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 29%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][NH2:38]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH:38][CH3:37])=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: CN
Product: CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and a saturated solution of methylamine (1.0 ml in DMF) were combined to give 26 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 512 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([O-:14])=[O:13].[NH4+].BrCC(C1C=CC=CC=1)=O>S(=O)(=O)(O)O.C(N)=O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=C(CBr)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: NC=O
Product: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1

Procedure:
Prepared by nitrogenating 4-phenyl-imidazole in concentrated sulphuric acid with ammonium nitrate analogously to Example D (64% of theory; melting point: 220° C.) or by heating ω-bromo-acetophenone in formamide (160° C., 2.5 hours) (53% of theory; melting point: 220-222° C.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.Cl[P:13](Cl)[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][CH:15]=1.[OH-].[Na+]>CCOCC>[PH2:13][C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][CH:15]=1
Reactant: ClP(Cl)c1csc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Pc1csc2ccccc12

Procedure:
Under a nitrogen atmosphere a three necked 1 L flask was charged with diethyl ether (200 ml) and a solution of LiAlH4 in THF (58 mL of 1 N solution, 58 mmol). A solution of 3-bis(chloro)phosphino benzo[d]thiophene (18.24 g, 77.6 mmol) in ether (ca. 40 mL) was added dropwise over ca. 30 minutes. An exothermic reaction took place, and a solid formed. The excess LiAlH4 was hydrolyzed by the dropwise addition of NaOH (15 ml 4 N solution) which led to the formation of a colourless solid which precipitated readily. The supernatant was removed via cannula, and the solid was extracted with another 20 ml of ether. Evaporation of the solvent in vacuo left the crude phosphine as a mobile oil which was further purified by vacuum destillation. Yield: 11.31 g (87%), b.p. 93° C., 0.036 mbar. 1H-NMR (C6D6, 300 MHz) δ 3.59 (dd, 2 H, 1JP,H=200.5 Hz, 4J=1.2 Hz, PH2); 7.10 (“tr”, 1 H, J=7.4 Hz, H-6); 7.19 (“dtr”, 2JH,P=7.5 Hz, 4J=1.2 Hz, H-2); 7.20 (tr, 1 H, J=7.4 Hz, H-5); 7.57 (d, 1 H, J=7.5 Hz, H-7); 7.70 (d, 1 H, J=7.5 Hz, H-4). 13C-NMR (C6D6, 75 MHz) δ 122.06 (d, J=16.1 Hz, C-2); 122.693 (C-7); 123.72 (C-4); 124.60, 124.63 (C-5, C-6), 134.54 (d, J=35 Hz, C-2); 140.75 (d, J=2.6 Hz, C-8); 142.22 (d, J=2 Hz, C-9). 31P{1H}-NMR (C6D6, 121 MHz) δ−163.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]([F:30])([F:29])[CH:17]([NH2:28])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[S:11]([NH:28][CH:17]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:16]([F:15])([F:29])[F:30])(=[O:13])=[O:12]
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: COc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(Cl)c1S(=O)(=O)NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
To a solution of 50 mg (0.18 mmol) of 2,4-dichloro-6-methoxybenzenesulfonyl chloride in 4 mL of pyridine was added 42 mg (0.19 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine. The mixture stirred for 6 hours at room temperature and was then diluted with 10 mL of ethyl acetate and washed with four 30 mL portions of 10% acetic acid, two 30 mL portions of saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted and concentrated in vacuo. The crude material was purified by filtering through a pad of silica eluting with ether. The material from the pad was dissolved in ether, and precipitated by slow evaporation which afforded 50 mg (57%) of the title compound as a bright yellow powder. MS: m/z 467 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([NH:19][C:20]([C:22]4[N:23]=[CH:24][S:25][CH:26]=4)=[O:21])[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1)=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>C1COCC1.C(O)C.C(O)(=O)C>[O:30]1[CH2:31][CH2:32][N:27]([CH2:1][C:3]2[CH:4]=[C:5]([C:9]3[CH:18]=[CH:17][C:16]4[C:11](=[C:12]([NH:19][C:20]([C:22]5[N:23]=[CH:24][S:25][CH:26]=5)=[O:21])[CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:28][CH2:29]1
Reactant: O=Cc1cccc(-c2ccc3cccc(NC(=O)c4cscn4)c3n2)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(Nc1cccc2ccc(-c3cccc(CN4CCOCC4)c3)nc12)c1cscn1
Reaction time: 18 h
Yield: 71.2 %

Procedure:
A solution of N-(2-(3-formylphenyl)quinolin-8-yl)thiazole-4-carboxamide (54 mg, 0.150 mmol) and morpholine (37 μL, 0.450 mmol) in a mixture of THF (4 mL) and Ethanol (8 mL) was added Na(OAc)3BH (95 mg, 0.450 mmol). The reaction was stirred 18 hours, and NaBH4 (17 mg, 3 eq) and acetic acid (500 uL) and the reaction was stirred for 2 hours. The reaction was quenched with water/methanol mixture, concentrated to dryness, and diluted with CH2Cl2. The resulting solution was washed with 1N NaOH, water, brine, dried (Na2SO4) and concentrated. The crude material was purified by silica gel column chromatography (0 to 10% methanol gradient in CH2Cl2 modified with 0.1% triethylamine). The product was lyophilized in a mixture of acetonitrile/water to obtain N-(2-(3-(morpholinomethyl)phenyl)quinolin-8-yl)thiazole-4-carboxamide (46 mg, 71% yield). MS (ESI) calcd for C24H22N4O2S (m/z): 430.15. found: 431 [M+1].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:18]([N:20]1[C:32]2[CH:31]=[CH:30][C:29]([NH2:33])=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([NH:33][C:29]2[CH:30]=[CH:31][C:32]3[N:20]([CH2:18][CH3:19])[C:21]4[C:26]([C:27]=3[CH:28]=2)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:16])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(NC(=O)CCCC(=O)O)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 55.7 %

Procedure:
To a solution of the compound obtained in Step 1 (200 mg, 0.97 mmol), 9-ethyl-9H-carbazol-3-amine (217 mg, 1.03 mmol) and DIEA (0.451 mL, 2.58 mmol) in DMF (6 mL) was added HATU (491 mg, 1.29 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (229 mg, 0.540 mmol, 62.7%) as a white powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][C:21]#[N:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]=1)#[N:24]>C1COCC1>[C:23]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]1[CH:20]([C:21]#[N:22])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:24]
Reactant: N#CC1=CCCc2ccccc21
Reactant: N#CCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC(Cc1ccccc1)C1CCc2ccccc2C1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 3.5 mL (25 mmol) of diisopropylamine in 40 mL of THF at -78° C., under a nitrogen atmosphere, was added n-butyllithium (9.5 mL of a 2.5M solution in THF, 23.7 mmol) and the resultant solution was stirred at -78° C. for 0.5 h. To the stirred solution was slowly added a solution of 2.75 g (21 mmol) of 3-phenylpropiononitrile in 40 mL of THF. The reaction mixture was stirred for 45 min at -78° C. and then a solution of 3.1 g (20 mmol) of 1-cyano-3,4-dihydronaphthalene (the product of Step 1 of Example 9) in 40 mL of THF was added. The reaction mixture was stirred at -78° C. for 0.5 h and then the reaction was quenched by pouring the reaction mixture into saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5.70 g (quantitative yield) of the title compound as a mixture of three diastereomers; MS DCl--NH3M/Z: 287 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:46]([CH3:47])=[CH:45][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH:34]4[CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]4)[N:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.CCOC(C)=O>C(O)(C)C.O1CCOCC1>[NH:36]1[CH2:37][CH:34]([N:30]2[C:31]3[C:27](=[CH:26][C:25]([C:21]4[CH:20]=[C:19]([C:17]5[S:18][C:14]6[C:13]([C:48]7[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=7)=[C:12]([C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:46]([CH3:47])=[CH:45][C:15]=6[N:16]=5)[CH:24]=[CH:23][N:22]=4)=[CH:33][CH:32]=3)[CH:28]=[N:29]2)[CH2:35]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C5CN(C(=O)OC(C)(C)C)C5)c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5C5CNC5)c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of (S)-tert-butyl 3-(5-(4-(6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)pyridin-2-yl)-1H-indazol-1-yl)azetidine-1-carboxylate (54 mg, 0.070 mmol) in isopropanol (3 mL) was added HCl in Dioxane (3 mL, 4 N in dioxane). The reaction mixture was stirred at room temperature. After the reaction finished, the reaction mixture was diluted by EtOAc, washed by saturated NaHCO3, back-extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give the product. LCMS-ESI+: calc'd for C37H36ClN5O3S: 666.2 (M+H+); found: 666.3.