Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1cccnc1
Yield: 91.9 %

Procedure:
3-Pyridylsulfonic acid (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole), suspended in 150 mL toluene and heated to reflux overnight. The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 30.7 g (92%) of 23-10 as a yellow oil, which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCCC1.C(OCC)(=O)C>[CH:18]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])(=[O:10])=[O:9])=[CH:4][N:3]=1)=[CH2:19]
Reactant: O=S(=O)(c1ccc(Cl)nc1)c1ccccc1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(S(=O)(=O)c2ccccc2F)cn1
Temperature: 150 °C
Yield: 66.2 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 1 Steps 1 and 2, 410 mg, 1.52 mmol), tributyl(vinyl)tin (535 mg, 1.69 mmol) and tetrakis-(triphenylphosphine)palladium(0) (87 mg) were combined in tetrahydrofuran (10 mL) in three batches in 5 mL microwave vials. The vials were heated to 150° C. for 10 minutes in a Smith synthesiser microwave reactor. The combined reactions were diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution. The organic layers were dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using 10-20% ethyl acetate/isohexane gave 2-vinyl-5-[(2-fluorophenyl)sulfonyl]pyridine as a colourless solid (265 mg, 66%). δH (500 MHz, d6 DMSO): 9.03 (1H, s), 8.30 (1H, dd, J=1.4, 8.3 Hz), 7.51 (1H, td, J=7.9, 0.85 Hz), 7.43 (1H, dd, J=9.1, 10.6 Hz), 6.92 (1H, dd, J=10.7, 17.4 Hz), 6.43 (1H, dd, J=1.2, 17.4 Hz), 5.70 (1H, dd, J=1.2, 10.7 Hz); m/z (ES+) 364 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:38]1[CH:43]=[CH:42][CH:41]=[C:40](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Br:1][C:2]1[CH:3]=[C:4]2[C:15]3([CH2:19][S:18][C:17]([N:20]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:40]4[CH:39]=[N:38][CH:43]=[CH:42][CH:41]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
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: [K+]
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1=NC2(CS1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial was charged with 3-bromo-7-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.114 g, 0.155 mmol), pyridin-3-ylboronic acid (0.029 g, 0.233 mmol), potassium carbonate (0.107 g, 0.776 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.016 mmol). The vial was flushed with Ar (g), then dioxane (1.035 mL) and water (0.517 mL) were added in sequence. The vial was sealed and heated at 80° C. for 2 hrs. After cooling to RT the reaction was diluted with EtOAc (25 mL) and washed with water (25 mL). The aqueous layer was extracted with EtOAc (3×15 mL), and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep 40 g, gradient elution 0-5% MeOH:DCM) to afford 3-bromo-7-(pyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:33]#[C:34][CH2:35][CH2:36][CH3:37])[CH:17]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: C#CCCC
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)OCC)c(Cl)c2)c1

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 1-pentyne (0.10 g; 1.47 mmol), bis(triphenyl-phosphine)palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 120 mg. HPLC-MS: m/z: 532.0 (M+); Rt: 2.02 min.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:22]2[S:23][CH:24]=[C:25]([Br:27])[N:26]=2)[CH2:18][O:17][C@@H:16]([CH3:19])[CH2:15][C@H:14]1[CH2:20][OH:21]>ClCCl>[Br:27][C:25]1[N:26]=[C:22]([C@@:13]2([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:11])[C@H:14]([CH2:20][OH:21])[CH2:15][C@H:16]([CH3:19])[O:17][CH2:18]2)[S:23][CH:24]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[C@H]1C[C@@H](CO)[C@](N)(c2nc(Br)cs2)CO1
Solvent: ClCCl
Product: C[C@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)c2ccccc2)(c2nc(Br)cs2)CO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzoyl isothiocyanate (6.92 g, 42.4 mmol) was added in a drop-wise manner to a solution of C4 (14.48 g, 47.13 mmol) in dichloromethane (420 mL), and the reaction mixture was stirred at room temperature for 24 hours. Volatiles were removed in vacuo, and the residue was purified via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane), providing the product as a yellow solid. Yield: 14.7 g, 31.2 mmol, 66%. 1H NMR (400 MHz, CDCl3) δ 11.70 (br s, 1H), 8.93 (br s, 1H), 7.86-7.90 (m, 2H), 7.62-7.67 (m, 1H), 7.51-7.56 (m, 2H), 7.25 (s, 1H), 5.47 (d, J=11.9 Hz, 1H), 3.91 (d, J=12.0 Hz, 1H), 3.83 (d, J=4.4 Hz, 2H), 3.74-3.81 (m, 1H), 2.44-2.52 (m, 1H), 1.80-1.87 (m, 2H), 1.33 (d, J=6.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:23][C:24]1[NH:28][N:27]=[N:26][N:25]=1>>[NH:25]1[C:24]([NH:23][C:16]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:15]=2)=[O:18])=[N:28][N:27]=[N:26]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)c1cccc(-c2cccc([N+](=O)[O-])c2)n1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nnn[nH]1)c1cccc(-c2cccc([N+](=O)[O-])c2)n1
Yield: 96.1 %

Procedure:
In the same manner as described in Example 13-(1), 6-(3-nitrophenyl)-2-pyridinecarboxylic acid (4.0 g), thionyl chloride (12 ml) and 5-aminotetrazole (1.54 g) are reacted to give N-(5-tetrazolyl)-6-(3-nitrophenyl)-2-pyridinecarboxamide (4.9 g). M.P. 275°-279° C. (decomp.)
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:19][CH:18]=1.[I:34]I>C1COCC1.O>[F:16][C:17]1[C:18]([I:34])=[CH:19][C:20]([O:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1
Reactant: COCCOCOc1ccc(F)nc1C(F)(F)F
Reactant: II
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc(I)c(F)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43.3 %

Procedure:
A dry 100 mL, 3-neck round bottom flask was fitted with an additional needle/septa, and inert atmosphere inlet, and a septa. The flask was charged with 2,2,6,6-tetramethylpiperidine (0.47 ml, 2.8 mmol), 5 mL dry THF and a stirbar. The flask was immersed in a ice-water bath and treated with a 1.6 M solution of butyllithium in hexanes (1.4 ml, 2.2 mmol) added over 15 minutes via syringe pump. The solution was stirred an additional 5 minutes and the ice-water bath was replaced with a dry ice acetone bath. To the stirring cold solution was added 6-fluoro-3-((2-methoxyethoxy)methoxy)-2-(trifluoromethyl)pyridine (0.5030 g, 1.9 mmol) dissolved in 5 mL dry THF over 2 minutes. The reaction was stirred for 1 h at −78° C. after which time a solution of iodine (0.12 ml, 2.2 mmol) dissolved in 5 mL dry THF was added via cannula over a 3 minute period. The reaction was stirred for 15 minutes, and then the cooling bath was removed. After stirring 5 minutes, the solution was poured onto sodium thiosulfate (1.8 ml, 19 mmol) dissolved in 50 mL water. The mixture was stirred for 10 minutes, and the layers were separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were washed with water (3×20 mL) and dried over MgSO4. The slurry was filtered and the filtrate was concentrated in vacuo. The sample was purified in one injection using a Waters Xterra Prep C18 MS Packed by Vydac/The Separations Group, 50 mm×300 mm (PN PA0000-050730), 10 μm particle size, spherical shape. 0→4 min@20 mL/min, 40% B; 4→5 min, 20→100 mL/min@ 40% B; 5→25 min@100 mL/min, linear gradient to 70% B; 25→35 min 100 mL/min, isocratic at 70% B; 35 min, step to 100% B @100 mL/min; 35→50 min@ 100 mL/min, 100% B; 50 min, step to 40% B @ 100 mL/min; 60 min end. A fraction that eluted from 24.4 to 26.1 minutes was isolated. The solvent was removed in vacuo to afford 2-fluoro-3-iodo-5-((2-methoxyethoxy)methoxy)-6-(trifluoromethyl)pyridine (0.3253 g, 44% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.39-3.42 (m, 3H) 3.60-3.65 (m, 2H) 4.00-4.06 (m, 2H) 5.26 (s, 2H) 7.65 (dd, J=4.11, 0.49 Hz, 1H). 19F NMR (376 MHz, chloroform-d) δ ppm −71.79 (d, J=3.90 Hz, 1 F)-65.02 (s, 3 F). 13C NMR (101 MHz, chloroform-d) 8 ppm 59.09 (s, 1 C) 70.25 (s, 1 C) 71.47 (s, 1 C) 100.53 (dq, J=1.73, 1.59 Hz, 1 C) 109.88 (d, J=8.67 Hz, 1 C) 119.98 (dq, J=275.70, 1.30 Hz, 1 C) 124.54 (dq, J=40.53, 1.08 Hz, 1 C) 137.97 (qd, J=35.04, 14.09 Hz, 1 C) 150.60 (d, J=5.20 Hz, 1 C) 157.42 (dq, J=245.79, 0.87 Hz, 1 C).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]23)[CH:23]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Product: FC(F)(F)c1ccccc1-c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-(trifluoromethyl)phenylboronic acid and following the procedures described in EXAMPLE 7, Parts B and C, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 147. 1H NMR (CDCl3) δ: 9.50 (broad s, 1H), 9.30 (broad s, 1H), 7.68 (d, 1H, J=8.1 Hz), 7.50 (t, 1H, J=7.3 Hz), 7.40 (t, 1H, J=7.3 Hz), 7.26 (d, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 3.80 (ABq, 2H, JAB=15.8 Hz), 3.61-3.45 (m, 2H), 3.37-3.05 (m, 6H), 2.90-2.80 (m, 1H), 2.70-2.57 (m, 1H), 2.25-2.10 (m, 2H). LRMS (ES)+: 391.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.O1CCCC1.[OH-].[NH4+:34]>>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH2:34])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyano-benzoxazinone product of Example 3, Step F) (100 mg, 0.25 mmol) tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 55 mg of the title compound, a compound of the present invention, as a white solid that decomposes in the melting apparatus above 255° C.
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH:8]2[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].[K+].[Br-]>CO>[CH:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH:8]2[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: O=C1NC(c2ccccc2)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: O=C1NC(C2CCCCC2)C1O
Temperature: 90 °C
Reaction time: 120 h

Procedure:
A suspension of 500 mg (3.06 mmol) of 4-phenyl-3-hydroxy-2-azetidinone VIa and 15 mg of Rh--C in 10 mL of methanol was heated at 90° C. under 800 psi in an autoclave. After 5 days, the hydrogen pressure was released and the catalyst filtered on celite. Evaporation of the solvent afforded a solid which was recrystallized in ethyl acetate to give 440 mg (85%) of VIIe as a white solid: White solid; mp 140°-140.5° C.; [α]D20 +65.1° (c 0.66, CH3OH); 1H NMR (250 MHz, MeOH-d4) δ 0.75-1.10 (m, 2H), 1.12-1.35 (m, 3H), 1.40-2.00 (m, 6H), 3.28 (dd, J=9.7, 4.6 Hz, 1H), 4.81 (d, J=4.6 Hz, 1H); 1H NMR (250 MHz, DMSO-d6) δ 0.75-1.00 (m, 2H), 1.10-1.35 (m, 3H), 1.37-1.55 (m, 1H), 1.58-1.85 (m, 5H), 3.10 (dd, J=9.6, 4.7 Hz, 1H), 4.67 (m, 1H), 5.87 (d, J=7.8 Hz, 1H), 8.21 (bs, 1H); 13C NMR (63 MHz, DMSO-d6) δ 25.08, 25.36, 26.07, 28.83, 29.17, 37.51, 59.04, 76.41, 170.21; IR (KBr) 3312, 3219, 2928, 1726 cm-1. Anal. Calcd for C9H15NO2 : C, 63.88, H, 8.93, N, 8.28. Found: C, 63.70, H, 9.00, N, 8.06.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1)[CH3:5].C(Cl)(Cl)Cl.[CH3:24][NH:25][C:26]([NH2:28])=[S:27].C(=O)(O)[O-].[Na+]>CO.[Na+].[Cl-]>[CH3:24][NH:25][C:26]1[S:27][CH:2]=[C:3]([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([F:18])[CH:7]=2)[CH3:5])[N:28]=1
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Reactant: CNC(N)=S
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 70 %

Procedure:
A mixture of (+)-1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (27.7 mg, 0.1 mmol; [α]D25 ° C.+180° (c=0.744, CHCl3), N-methylthiourea (9 mg, 0.1 mmol) and sodium bicarbonate (9.2 mg, 0.11 mmol) in methanol (1 ml) was stirred at room temperature for 28 hr and the mixture was diluted with NaCl aq., then extracted with ethyl acetate. The extracts were dried with magnesium sulfate and evaporated under reduced pressure to a residue, which was chromatographed to afford (+)-2-methylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (21.9 mg, 70% yield): [α]D25 ° C.+10.7° (c=0.15, CHCl3); 70% ee.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]1[C:13]2[CH:14]=[CH:15][C:16]([N:18]=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][C:12]=2[CH2:11][CH2:10][O:9]1)(=O)=O.[F:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([N:43]1[CH2:48][CH2:47][NH:46][C@H:45]([CH3:49])[CH2:44]1)=[CH:38][CH:37]=[CH:36]2>>[C:26]1([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][C:16]2[CH:15]=[CH:14][C:13]3[C@H:8]([CH2:7][CH2:6][N:46]4[CH2:47][CH2:48][N:43]([C:39]5[C:40]6[C:35](=[CH:34][C:33]([F:32])=[CH:42][CH:41]=6)[CH:36]=[CH:37][CH:38]=5)[CH2:44][C@H:45]4[CH3:49])[O:9][CH2:10][CH2:11][C:12]=3[CH:17]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N=C(c3ccccc3)c3ccccc3)ccc21

Procedure:
2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-2-benzopyran-1-yl}ethyl methanesulfonate was coupled with (3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine, as described for Example 1b), to yield (1S)-N-(diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4].[K+].[N+:21]([O-])([OH:23])=[O:22]>C(OCC)C>[CH3:1][O:2][C:3]([CH2:5][C:6]1[C:15]2[C:10](=[C:11]([N+:21]([O-:23])=[O:22])[CH:12]=[CH:13][CH:14]=2)[C:9]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:8][CH:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccc(S(=O)(=O)[O-])c2ccccc12
Reactant: O=[N+]([O-])O
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)Cc1ccc(S(=O)(=O)O)c2c([N+](=O)[O-])cccc12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Potassium 1-(methoxycarbonylmethyl)-4-naphthalene sulfonate (10 g, 31.4 mmol) was added portionwise over 30 minutes to 90% nitric acid, which was cooled in a methanol/ice bath to approximately−15° C. After 2 hours, the bath temperature had reached −10° C. and diethyl ether (200 mL) was added to the mixture. The precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 70:30 mixture of the 5- and 8-nitro isomers (approximately 12 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[N:12][CH:13]=1)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[N:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCC#Cc1ccc(C#CCNC(C)=O)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCCc1ccc(CCCNC(C)=O)nc1
Yield: 98.1 %

Procedure:
A mixture of N-(3-{5-[3-(acetamido)prop-1-ynyl]pyridin-2-yl}prop-2-ynyl)acetamide (2-1) (10 g), 10% Pd/C (1.5 g) in methanol (200 mL) was hydrogenated under 20 psi hydrogen at room temperature for 16 hours. The catalyst was removed by filtration using Solka-floc and washed with methanol. The filtrate and washings were combined and concentrated under reduced pressure to provide 10-1 as a crystalline compound (10.1 g); m.p. 95.2-97.8° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
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: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)c(F)c3)c(C(=O)Nc3cccnc3)c2)cn1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-([(3,4-difluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 60; 120 mg, 0.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (65.5 mg, 0.32 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.57 ml, 0.57 mmol) and tetrakis(triphenylphosphine)palladium(0) (19.85 mg, 0.017 mmol). The vial was sealed and heated to 120° C. for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using the MDAP to yield the title compound. 28 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)[C:4]([CH3:18])=[N:3]1.[CH3:19][NH:20][CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:19][N:20]([CH3:21])[CH:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[C:4]([CH3:18])=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CNC
Reactant: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(N(C)C)CC2

Procedure:
(Method 2): 6-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-indan-1-one (1.1 mmol) was dissolved in MeOH. Dimethyl-amine (24.5 mmol), acetic acid (0.11 mmol) and sodium cyanoborohydride (2.2 mmol) were added under argon atmosphere. The suspension was refluxed overnight and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion™ system to yield the base of the title compound. The obtained product was diluted in ethyl acetate and a solution of hydrogen chloride 2.0 M in diethylether was added. The resulting precipitate was filtered and dried under vacuum to yield the title compound dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine dihydrochloride (79%). MS [MH]+=270.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:31])[C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[I-:32].[NH+]1C=CC=C[CH:34]=1>C(OCC)C>[I-:32].[C:1]([CH2:3][NH:4][C:5]([C@@H:6]([O:11][C@H:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N+:21]([CH3:34])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:31])#[N:2]
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2cccnc2)cc1)C(=O)NCC#N
Reactant: c1cc[nH+]cc1
Agent: [I-]
Solvent: CCOCC
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(-c2ccc[n+](C)c2)cc1)C(=O)NCC#N

Procedure:
Using the same procedure as described for example 36 step 3 (2S)-N-(cyanomethyl)-4-methyl-2-{[(R)-phenyl(4-pyridin-3-ylphenyl)methyl]oxy}pentanamide (150 mg, 0.36 mmol) was converted to its pyridinium iodide salt. The salt was swished with diethyl ether (20 mL) for 18 h and the title compound was filtered off as an amorphous solid.