Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]3[CH2:27][C@H:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([O:36]CC4C=CC([N+]([O-])=O)=CC=4)=[O:35])[CH2:25][N:24]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:22])[CH2:17][CH2:16]2)[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:19][CH2:20]1)(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1
Yield: 38 %

Procedure:
5.10 g of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 100 ml of a 6:4 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2.5 hours in the presence of 5.0 g of 10% w/w palladium-on-charcoal. The catalyst was filtered off, and the filtrate was washed with diethyl ether and then concentrated by evaporation under reduced pressure. The resulting residue was purified by reverse phase column chromatography through 250 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using water, 5% v/v aqueous acetonitrile and 7% v/v aqueous acetonitrile, in that order, as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized to give 940 mg of the title compound, as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12](I)[CH:13]=[CH2:14].[H-].[Na+]>CN(C=O)C>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:13]=[CH2:12]
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 3-hydroxybenzoate (5.0 g, 32.9 mmol) in DMF (20 mL) was added allyl iodide (6.62 g, 39.4 mmol) followed by sodium hydride (60% oil dispersion, 0.95 g, 39.4 mmol). After stirring at rt for 5 h, the reaction mixture was quenched with H2O, extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum. Purification by silica gel chromatography (10% EtOAc/hexanes) afforded the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>N1C=CC=CC=1>[CH2:27]([NH:29][C:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([O:14][CH3:15])[N:13]=2)[CH:3]=1)=[O:31])[CH3:28]
Reactant: CCN=C=O
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.8 %

Procedure:
To a solution of [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine (184 mg, 0.45 mmol, Example 2) in pyridine (1.5 mL) is added ethyl isocyanate (43 μL, 0.54 mmol). The reaction mixture is stirred for 18 hours at ambient temperature, quenched with the addition of water (25 mL), and extracted four times with EtOAc (25 mL). The combined extracts and washed four times with aqueous copper sulfate solution (25 mL), with water (25 mL), with brine (25 mL), dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica (4.5 g) eluting with 20 to 40% EtOAc in heptane to afford 1-ethyl-3-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-urea [98.3 mg, 52%, Example 41]. LCMS: RT=2.68 minutes, MS: 422 (M+H). 1H NMR (300 MHz, CDCl3), δ 8.11 (1H, d, J=0.17 Hz), 7.88 (2H, s), 7.62 (1H, d, J=0.026 Hz), 7.49 (1H, d, J=0.026 Hz), 7.18 (4H, m), 6.81 (2H, m), 6.22 (1H, d, J=0.08 Hz), 5.83 (1H, s), 5.35 (1H, s), 3.93 (3H, d, J=0.04 Hz), 3.73 (3H, d, J=0.012 Hz), 3.55 (2H, m), 3.19 (2H, q, J=0.022 Hz), 2.81 (2H, m), 2.13 (1H, s), 1.04 (2H, t, J=0.022 Hz). IC50=7.6 nM
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:21](O)=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)=[O:8].CN.O.O[N:30]1[C:34]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:21]([NH:30][CH3:34])=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2ccccc2)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:15][O:16][CH3:17])[CH:8]=[O:9]
Reactant: COCCl
Reactant: CN(C)c1cc(C=O)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1N(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (60% in oil, 1.90 g, 47.5 mmol) in dry DMF (60 ml) was added dropwise a solution of the compound (3) (5.98 g, 36.2 mmol) obtained above in DMF (40 ml) under nitrogen atmosphere under ice-cooling. The mixture was stirred at 0° C. for 30 minutes, and thereto was added dropwise chloromethyl methyl ether (3.6 ml, 47.4 mmol). The reaction mixture was stirred at 0° C.-room temperature for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The concentrate was purified by column chromatography on silica gel to give the title aldehyde compound (Compound A) as yellow liquid. Yield 7.17 g (95%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH:14]=[N:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH3-]C#N.[Na+].O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([S:21][CH3:22])[CH:19]=3)[CH2:14][NH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSc1ccc2cnnc(-c3ccc(NC(C)=O)cc3)c2c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc2c(c1)C(c1ccc(NC(C)=O)cc1)=NNC2
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
To a solution of the phthalazine 7 (130 mg, 0.42 mmol) in acetic acid (7 mL) was added NaBH3CN in portions. After stirring for 15 min, water was added. The aqueous phase was neutralized by NaHCO3, and then extracted with DCM. The combined organic phase was dried over Na2SO4. Removal of the solvent afforded the product (97 mg, 74%) which can be used directly for next step.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1>C(OCC)C.CS(C)=O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1([CH2:14][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH2:4][O:16]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Sodium hydride (3.78 g, 0.079 mole as 50% dispersion in oil) was suspended, with stirring, in 20 ml of dry diethyl ether. The ether was then removed by decantation, and the sodium hydride was dried in a stream of dry nitrogen. 100 Ml of dry dimethyl sulphoxide was added followed by 17.34 g (0.079 mole) of dry powdered trimethylsulphoxonium iodide, in portions, over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20° C.). 2-(1H-1,2,4-Triazol-1-yl)-2',4'-dichloroacetophenone (18.33 g, 0.072 mole) as a solution in 50 ml of dry dimethyl sulphoxide was then added. The mixture was heated at 60° C. for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was cooled and quenched in ice and the product was then extracted into ethyl acetate (600 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, and concentrated to give a red gum. Column chromatography of the gum on silica, eluting with ether, gave 6.62 g (34.4%) of the title compound as a gum.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:11]2[CH:15]=[N:14][C:13]([N+:16]([O-:18])=[O:17])=[N:12]2)=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[C:19]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:16]([C:13]1[N:14]=[CH:15][N:11]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[CH2:19])=[CH:10][C:7]=2[C:8]#[N:9])[N:12]=1)([O-:18])=[O:17]
Reactant: N#Cc1cc(C=O)ccc1-n1cnc([N+](=O)[O-])n1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cnc([N+](=O)[O-])n2)c(C#N)c1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a stirred solution of 5-formyl-2-(3-nitro-1H-1,2,4-triazol-1-yl)benzonitrile (0.36 g, 1.49 mmol) in 1,4-dioxane (25 mL), were added K2CO3 (0.3 g, 2.2 mmol) and methyl triphenyl phosphonium bromide (0.63 g, 1.79 mmol). The resultant reaction mixture was heated to 100° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afford the title compound as a solid (0.25 g, 70%): mp 103-105° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.34 (m, 1H), 7.98 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 6.87 (m, 1H), 6.20 (d, J=15.7 Hz, 1H), 5.56 (d, J=11.8 Hz, 1H); ESIMS m/z 240.27 ([M−H]−); IR (thin film) 2240, 1514, 1312 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[N:9]O)[CH2:7][O:8][C:4]=2[CH:3]=1.[H][H]>O1CCCC1.CO.[Ni]>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]([NH2:9])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: ON=C1COc2cc(F)ccc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: NC1COc2cc(F)ccc21
Yield: 33.7 %

Procedure:
A mixture of the above described 6-fluoro-benzofuran-3-one oxime (5.38 g, 32 mmol; HPLC 1.489 min) and Raney-Nickel (2.4 g) in tetrahydrofuran (125 mL) and methanol (125 mL) was hydrogenated at 100 bar hydrogen-pressure at 50° C. for 18 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles very removed in vacuum to give the crude product which was purified by Si—NH2 column chromatography with n-heptane/ethyl acetate to give the title compound as a light brown liquid (1.65 g, 34%, HPLC 0.367 min 100%), MS (ISP) m/e=154.0 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](=[S:19])=[S:18].[OH-].[K+:21].C(OCC)(=O)C>CN(C)C=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]([S-:19])[S-:18])(=[O:14])=[O:15].[K+:21].[K+:21]
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 166.3 %

Procedure:
115.5 g of 2-phenylbenzenesulfonamide were dissolved in 500 ml of dimethylformamide, and 38 g of carbon disulfide and 28 g of potassium hydroxide were added to the resulting solution. The mixture was stirred at room temperature for 7 hours. Potassium hydroxide (28 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, 400 ml of ethyl acetate were added dropwise to precipitate pale yellow crystals. The crystals were filtered, and washed with ethyl acetate to give 160 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate represented by the following formula: ##STR25##
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][O:54][CH2:55][CH2:56][NH2:57].[BH3-]C#N.[Na+]>>[CH3:53][O:54][CH2:55][CH2:56][NH:57][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: COCCN
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 50.4 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(11) (4.4 mg, 0.00723 mmol) to give 15 mg of the title compound (46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH:11]([NH:14][CH2:15][C:16](O)=[O:17])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[CH2:15][N:14]([CH:11]([CH3:13])[CH3:12])[C:9]2=[S:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CC(C)NCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)N1CC(=O)N(c2ccc(F)cc2)C1=S
Yield: 50 %

Procedure:
The title compound was prepared by the procedure described in Example 45 using 15.3 g of 4-fluorophenyl-isothiocyanate,. 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (12.6 g) as a peach solid, m.p. 184°-186° C. Anal. Calcd. for. C12H13F N2O S: C, 57.12; H, 5.19; N, 11.10. Found: C, 56.98; H, 5.09; N, 11.06. Mass spectrum (+FAB, [M+H]+) m/z 253.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([O-:9])=[O:8])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.C[C@H]([NH3+])C1C=CC=CC=1.Cl.CCO>O>[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:9])=[O:8])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: O=C([O-])[C@H]1CC[C@@H](O)[C@@H]1c1ccc(F)cc1
Agent: C[C@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1CC[C@@H](O)[C@@H]1c1ccc(F)cc1

Procedure:
The salt from Step B was dissolved in water and acidified with 2N HCl and was extracted with 3 portions of ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to give a white solid. [α]D (EtOH)=+21.6 (c=2.55).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]2=[C:15]3[N:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9][CH2:8][CH2:7][C:6]3=[CH:5][C:4]=1[CH:16]=[CH:17][C:18]1[S:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1.[C:25]([C:27]1[C:28](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:33]([F:36])([F:35])[F:34])[C:31]=1[CH3:32])#[N:26]>C(O)C.O1CCCC1>[C:25]([C:27]1[C:28](=[C:43]([C:46]#[N:47])[C:44]#[N:45])[O:29][C:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:33]([F:36])([F:34])[F:35])[C:31]=1[CH:32]=[CH:23][C:21]1[S:22][C:18]([CH:17]=[CH:16][C:4]2[CH:5]=[C:6]3[C:15]4[N:10]([CH2:9][CH2:8][CH2:7]3)[CH2:11][CH2:12][CH2:13][C:14]=4[C:3]=2[O:2][CH3:1])=[CH:19][CH:20]=1)#[N:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: COc1c(C=Cc2ccc(C=O)s2)cc2c3c1CCCN3CCC2
Solvent: CCO
Solvent: C1CCOC1
Product: COc1c(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)cc2c3c1CCCN3CCC2
Temperature: 60 °C
Yield: 44.9 %

Procedure:
In 5 ml of ethanol and 1.5 ml of tetrahydrofuran were dissolved 120 mg (0.35 mmol) of 5-[2-(8-methoxy-2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine-9-yl)vinyl]thiophene-2-carboaldehyde and 123 mg (0.39 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 60° C. for 3 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 100 mg of a dark brown crystal (yield: 44.4%; mp: 156-160° C.)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[N:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>C(Cl)Cl>[CH3:10][N:8]([CH3:9])[C:6]1[N:5]=[C:4]([O:11][CH3:12])[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:13])(=[O:22])=[O:21])=[O:25])[N:7]=1
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(N(C)C)n1
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2C)nc(N(C)C)n1
Reaction time: 24 h

Procedure:
To a stirred solution of 0.85 g of 2-amino-4-dimethylamino-6-methoxy-1,3,5-triazine in 40 ml of methylene chloride was added, dropwise, 1.0 g of 2-methylbenzenesulfonyl isocyanate in 10 ml of methylene chloride. After stirring 24 hours, the resulting solution was evaporated to yield a solid. Recrystallization from benzene/hexane yielded the product named above melting at 194°-198°.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19]O)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][Cl:23])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(CO)cnc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(CCl)cnc21
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of (1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-methanol (4.2 g, 14.6 mmol) in dichloromethane (20 mL) at 0° C. was added a solution of thionyl chloride (1.6 mL, 21.9 mmol) in dichloromethane (5 mL) and then stirred for 2 h. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution (2×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-5-chloromethyl-1H-pyrrolo[2,3-b]pyridine (3.3 g, 75%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C14H11ClN2O2S [M+H]+ 307.77, observed 307.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:20]3[CH:21]=[C:22]4[CH:28]=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[CH:13]=2)[CH:6]=[CH:5][N:4]=1.[H-].[Na+].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[C:31]1([S:37]([N:26]2[C:23]3=[N:24][CH:25]=[C:20]([C:10]4[C:9]([C:7]5[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=5)=[CH:13][N:12]([CH:14]5[CH2:19][CH2:18][CH2:17][CH2:16][O:15]5)[N:11]=4)[CH:21]=[C:22]3[CH:28]=[CH:27]2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3[nH]ccc3c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 25 °C

Procedure:
To a solution of the 5-[4-(2-Methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-1) (870 mg, 2.22 mmol) in DMF (10 mL) at 25° C. was added Sodium Hydride (60% dispersion in oil, 133 mg, 3.32 mmol). The resulting suspension was stirred at ambient temperature for a few minutes until gas evolution ceased. Benzenesulfonyl chloride (0.4 mL, 3.13 mmol) was added and the mixture became cloudy. After stirring at ambient temperature for 15 minutes, LCMS showed complete conversion to desired product. The mixture was added slowly to 150 ml of saturated aqueous NaCl. The resulting precipitate was filtered, washed with water, and air dried. The solids were dissolved in dichloromethane, dried over MgSO4 and reduced to minimum volume. The residue was purified on a short column of silica gel using a gradient of 0-20% ethyl acetate in dichloromethane as eluent to give 1-Benzenesulfonyl-5-[4-(2-methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-2) (0.83 g, 70%) as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (s, 1H), 8.47 (d, J=5.31 Hz, 1H), 8.43 (d, J=2.02 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 8.09-8.15 (m, 2H), 7.95 (d, J=4.04 Hz, 1H), 7.68-7.77 (m, 1H), 7.57-7.67 (m, 2H), 7.29 (d, J=5.05 Hz, 1H), 6.86 (d, J=4.04 Hz, 1H), 5.52 (dd, J=9.85, 2.27 Hz, 1H), 3.98 (br. d, J=11.87 Hz, 1H), 3.62-3.74 (m, 1H), 2.07-2.23 (br. m, 1H), 1.90-2.05 (br. m, 2H), 1.66-1.77 (br. m, 1H), 1.65 (s, 3H), 1.50-1.61 (br. m, 2H).
Reaction SMILES: [Br:1]Br.[C:3]1([C:9]2[CH:13]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C>[C:3]1([C:9]2[C:13]([Br:1])=[C:12]([S:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:11][N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: BrBr
Reactant: c1ccc(Sc2cc(-c3ccccc3)n[nH]2)cc1
Solvent: CC(=O)O
Product: Brc1c(-c2ccccc2)n[nH]c1Sc1ccccc1
Reaction time: 12 h
Yield: 96.7 %

Procedure:
At 25° C, 8 parts of bromine is slowly added, with stirring, to a solution of 12.6 parts of 3-phenyl-5-phenylthiopyrazole in 150 parts of glacial acetic acid. After 12 hours, the solution is concentrated in vacuo and the residue treated with about 50 parts of water. There is obtained 16 parts (96.7% of theory) of 3-phenyl-4-bromo-5-phenylthiopyrazole; m.p.: 121° to 122° C (recrystallized from cyclohexane).