Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (20.0 g, 102 mmol) in DMF (400 ml) at 0° C. was added NaH (60% mineral oil dispersion; 4.87 g, 122 mmol) slowly (CAUTION: GAS EVOLUTION). The reaction mixture was stirred at 0° C. for 2 h. Benzenesulfonyl chloride (17.0 ml, 132 mmol) was added dropwise, and the reaction mixture was allowed to warm to ambient. After 1 hour the reaction mixture was cooled in an ice bath, and 100 mL of water was added slowly (CAUTION: GAS EVOLUTION, EXOTHERM). The reaction mixture was partitioned between ethyl acetate (500 mL) and brine (600 mL). The organic layer was washed with additional brine (500 mL), followed by saturated aqueous ammonium chloride (250 mL). The first and 3rd aqueous layers were combined and back-extracted with ethyl acetate (500 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to a thick slurry. EtOAc (100 mL) was added, followed by hexanes (100 mL). The mixture was filtered, and the filter cake was rinsed with 1:1 EtOAc/Hexanes (50 mL) to afford 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine as a grey solid. The filtrate can be concentrated and purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford additional product. LRMS (ESI) calculated for C13H9BrN2O2S [M+H]+, 337.0; found 336.9.
Reaction SMILES: CS(C)=O.[C:5]([C:11]([O:13][CH3:14])=[O:12])#[C:6][C:7]([O:9][CH3:10])=[O:8].[NH2:15][C:16]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=[C:18]([S:27][CH3:28])[C:17]=1[C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:30][C:29]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:15]=[C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([S:27][CH3:28])[C:17]=12
Reactant: CSc1nn(-c2ccccc2)c(N)c1C#N
Reactant: COC(=O)C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nc2c(c(SC)nn2-c2ccccc2)c(N)c1C(=O)OC
Yield: 25.6 %

Procedure:
A dimethylsulfoxide (20 ml) solution of 9.0 g (63 mmol) of dimethyl acetylenedicarboxylate was dropwise added to a mixture comprised of 11.5 g (50 mmol) of 5-amino-3-methylthio-1-phenylpyrazole-4-carbonitrile, 20.8 g (145 mmol) of anhydrous potassium carbonate and 300 ml of dimethylsulfoxide, while stirring and cooling with ice, and then stirred for further 60 hours at room temperature. During the stirring, the reaction liquid was changed from brown to greenish brown. After the reaction, the liquid reaction mixture was poured into 500 ml of water with ice and stirred for 30 minutes at room temperature. The blackish brown solid thus precipitated was taken out, and 20 ml of methanol was added thereto and heated. The white crystals thus formed were taken out by means of filtration under suction and recrystallized from methanol to obtain 4.80 g (12.8 mmol) of the entitled product as colorless, needle-like crystals having a melting point of 120° to 122° C.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30])=O)C1C=CC=CC=1>C(O)(=O)C.C(OCC)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14]([CH3:29])[C:13]1=[O:30]
Reactant: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
A mixture of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (3.0 g) and hydrobromic add (45% in acetic acid, 6.2 ml) was stirred for 1 h at room temperature under an atmosphere of nitrogen. The mixture was then diluted with cold anhydrous diethyl ether (40 ml) and it was stirred at 0° C. for 45 min. The white precipitate was collected by filtration, washed with cold diethyl ether (4×30 ml) and then dissolved in a mixture of water (30 ml) and aqueous sodium hydroxide (2M, 15 ml). The basic aqueous phase was extracted with ethyl acetate (3×70 ml) and the combined organic layers were washed with brine (30 ml), dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel using 94:6, dichloromethane:methanol as the eluant, to afford the title compound (1.6 g). Mp 133°-136° C. 1H NMR (360 MHz, CDCl3) δ 1.02-1.40 (4H, m), 1.47-1.56 (1H, m), 1.61-1.74 (3H, m), 1.84-1.91 (1H, m), 1.96-2.06 (1H, m), 2.17 (2H, brs), 2.70-2.80 (1H, m), 3.39 (3H, s), 4.29 (1H, s), 7.20-7.27 (2H, m), 7.44-7.54 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:13][CH3:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[CH2:23][C:24](Cl)=[O:25].Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1([N:13]([C:24](=[O:25])[CH2:23][C:17]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=2[CH3:15])[CH3:14])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: CNC1(C(=O)OC)CCN(OC)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)C1(N(C)C(=O)Cc2cc(C)ccc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 1-methoxy-4-methylamino-piperidine-4-carboxylic acid methyl ester (200 mg, 0.99 mmol) in pyridine (5 ml) was added (2,5-dimethyl-phenyl)-acetyl chloride (240 mg, 1.31 mmol) dropwise at 0° C. The reaction mixture was stirred at 0° C. for one hour and at room temperature for 6 hours, poured on ice water, acidified to pH 7 with an aqueous 2N HCl solution and diluted with ethyl acetate (50 ml). The layers were separated, the aqueous phase extracted with ethyl acetate (3×25 ml), the combined organic phases washed with water (3×15 ml) and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 2:1). Yield: 170 mg of 4-{[2-(2,5-dimethyl-phenyl)-acetyl]-methyl-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (title compound P4.46) as a colorless gum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16]C)=[O:15])=[O:10])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([OH:16])=[O:15])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(C(=O)Nc2ccc(N)nc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1C(=O)Nc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To methyl 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoate (0.11 g, 0.39 mmol) dissolved in tetrahydrofuran (1.5 mL) was added a solution of lithium hydroxide, monohydrate (24 mg, 0.58 mmol) in water (1.5 mL). The reaction mixture was stirred at RT for 4 h. THF was removed in vacuo and to the aqueous layer was added 2N HCl until pH 4-5. The precipitate formed was collected by filtration, washed with water, dried to give 3-((6-aminopyridin-3-yl)carbamoyl)-4-methylbenzoic acid as a tan solid, MS (ESI, pos. ion) m/z: 272.1 (M+1).
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:11]1([O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25]C(C)CCC(O)=O)[C:20]2[C:15](=CC=CC=2)[CH:14]=[CH:13][CH:12]=1>>[CH3:22][O:21][CH2:11][CH2:12][C:14]1[CH:13]=[CH:12][C:11]([O:21][CH2:22][CH:23]([OH:33])[CH2:24][NH:25][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:20][CH:15]=1
Reactant: CC(=O)CCCCC(=O)O
Reactant: CC(CCC(=O)O)NCC(O)COc1cccc2ccccc12
Product: COCCc1ccc(OCC(O)CNC(C)CCCCC(=O)O)cc1

Procedure:
The title compound was synthesized from Compound V [R=4-(β-methoxyethyl)-phenyl] and 6-oxoheptanoic acid p-toluide on a 2 mmol scale using the general procedure described above for Compound 7.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.[H][H]>CN(C)C=O.CO.[Ni]>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]2[O:18][C:17](=[O:19])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:5]=2[CH:6]=1
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2oc(=O)c3c(c2cc1N)CCNC3
Yield: 81.2 %

Procedure:
A solution of 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (6.0 g, 0.023 moles) in N,N-dimethylformamide (100 ml) and methanol (50 ml) is hydrogenated at 50 psi in the presence of Raney Nickel (0.5 g) at room temperature for 20 hours. Additional Raney Nickel (0.5 g) in N,N-dimethylformamide (50 ml) is then added, and hydrogenation resumed until hydrogen uptake ceases. The catalyst is filtered off and rinsed with warm N,N-dimethylformamide. The filtrate is concentrated under reduced pressure and filtered to afford the product (4.3 g), mp 283°-284° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[CH:35].C(#N)C>C(Cl)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>[CH3:32][C:33]([CH3:37])([CH3:36])[C:34]#[C:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1
Reactant: C#CC(C)(C)C
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC#N
Product: COc1cnc2c(Oc3ccc(Nc4nnc(C#CC(C)(C)C)c5ccccc45)cc3)ccnc2c1
Temperature: 90 °C

Procedure:
A resealable pressure bottle, purged with argon, was charged with 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (120 mg, 0.28 mmol), bis(triphenylphosphine)palladium(ii) chloride (24 mg, 0.03 mmol), copper(I) iodide (6.4 mg, 0.03 mmol), 3,3-dimethyl-1-butyne (86 μl, 0.70 mmol), and ACN (2.8 mL, 0.1 M). To the mixture was added TEA (0.785 mL, 5.6 mmol). The reaction vessel was sealed and the mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to RT, diluted with DCM and filtered over Celite. The filtrate was concentrated under reduced pressure to give a brown residue, which was purified by Gilson HPLC {5-65% (0.1% TFA in CH3CN) in H2O over 20 min}. The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with DCM. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure 4-(3,3-dimethylbut-1-ynyl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine MS [M+H]=476.1 Calc'd for C29H25N5O2: 475.5.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])[CH2:3]1.[ClH:26].[N:27]1([C:32](N)=[NH:33])C=CC=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[ClH:26].[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:8]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:32](=[NH:27])[NH2:33])[CH2:14][CH2:13]2)=[O:9])[CH2:3]1
Reactant: N=C(N)n1cccn1
Reactant: O=C(OCC1CCNCC1)[C@](O)(c1ccccc1)[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N=C(N)N1CCC(COC(=O)[C@](O)(c2ccccc2)[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.3 %

Procedure:
To a solution of 14 mg of piperidin-4-ylmethyl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-phenylethanoate in 0.020 ml of anhydrous dimethylformamide, 6.3 mg of 1H-pyrazole-1-carboxamidine hydrochloride and 0.008 ml of diisopropylethylamine were added, followed by stirring at room temperature for 12 hours. The reaction liquid was condensed and dried to solid. Thus obtained crude product was purified on silica gel column chromatography (eluent: chloroform/methanol =10/1), to provide 11 mg of the title compound in the form of a colorless solid.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[Br:6][CH2:7][CH:8]([OH:10])[CH3:9]>C(Cl)(Cl)(Cl)Cl>[Br:6][CH2:7][CH:8]([O:10][P:1]([Cl:5])([Cl:3])=[O:2])[CH3:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(O)CBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC(CBr)OP(=O)(Cl)Cl
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a solution of 46 g of phosphorous oxychloride in 110 ml of carbon tetrachloride was added with stirring 21 g of 1-bromo-2-propanol. The mixture was stirred overnight, the solvent removed and the residue evaporated twice from toluene at 35° C., then evaporated to dryness giving a dark oil. This oil was distilled on a Kugelrohr at 75° C., 0.3 mm giving 16.3 g of the desired compound as a white oil.
Reaction SMILES: [C:1]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.[NH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:13])=[CH:14][CH:15]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with 4-pivaloylbenzoic acid (7.67 g, 37.2 mmol), ethyl 3-aminopropanoate hydrochloride (6.86 g, 44.6 mmol), HOAT (5.57 g, 40.9 mmol), DCM (93 mL) and TEA (7.80 mL, 55.8 mmol). EDC hydrochloride (7.92 g, 40.9 mmol) was then added in one portion and the reaction allowed to stir at room temperature for 2 hours. DCM added to the reaction mixture and organics washed with an ammonium chloride solution (sat. aq.; 1×), water (2×), brine (1×), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide ethyl 3-(4-pivaloylbenzamido)propanoate as a yellow oil (4.25 g, 37.4%; over 3 steps). 1H NMR (400 MHz, CDCl3) δ 1.26 (m, J=7.02, 7.02 Hz, 3H) 1.32 (s, 9H) 2.63 (t, J=5.95 Hz, 2H) 3.72 (m, J=6.05, 6.05, 6.05 Hz, 2H) 4.16 (m, J=7.22, 7.22, 7.22 Hz, 2H) 6.92 (br. s., 1H) 7.64-7.68 (m, 2H) 7.75-7.79 (m, 2H); MS (M+1): 306.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[C:4]([Br:12])[C:3]=1[O:13][CH3:14].Cl.Cl[Sn]Cl.O>C(O)C>[Br:12][C:4]1[C:3]([O:13][CH3:14])=[C:2]([Br:1])[CH:7]=[C:6]([F:8])[C:5]=1[NH2:9]
Reactant: COc1c(Br)cc(F)c([N+](=O)[O-])c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1c(Br)cc(F)c(N)c1Br
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To the solution of 8-4 (234.2 g, 0.784 mol) and concentrated HCl (720 mL) in ethanol (2.2 L) at room temperature, SnCl2.H2O (415 g, 2.0 mol) was added by portions. The mixture was stirred for 16 h. TLC showed the reaction was completed. The volatiles were removed in vacuo. The residue was quenched with cooled water (500 mL) and ethyl acetate (1.5 L). The aqueous layer was neutralized with KOH until PH=6˜7. The white precipitate was filtered off to get a clear solution, which was extracted with ethyl acetate (600 mL×3). The combined organic layers were washed with brine twice, dried over anhydrous sodium sulfate. After filtration and evaporation, 8-5 (212.7 g, 100%) was obtained as brownish white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[CH:11][N:5]2[N:4]=1.CO.[Br:23]N1C(=O)CCC1=O>C1COCC1>[Br:23][C:11]1[N:5]2[C:6]([CH:7]=[N:8][C:3]([S:2][CH3:1])=[N:4]2)=[C:9]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ncc2c(OCOCC[Si](C)(C)C)ccn2n1
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ncc2c(OCOCC[Si](C)(C)C)cc(Br)n2n1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine (1.05 g, 3.37 mmol), Tetrahydrofuran (50 mL) and Methanol (25 mL) were added and stirred at room temperature. N-Bromosuccinimide (0.630 g, 3.54 mmol) in THF (20 mL) was added to the reaction mixture . The reaction was stirred at room temperature for 2 hours. LCMS suggested no SM. The solvent was removed under vacuum. The reaction was partitioned with water and Et2O. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc as eluant (5 to 20% EtOAc). The collected fractions afforded 7-Bromo-2-methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine as an oil (1.10 g, 83%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:21])[CH3:20])[S:16]2)[C@@H:12]([OH:22])[C@@H:11]1[OH:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:20])[CH3:21])[S:16]2)[C@@H:12]([O:22][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:11]1[O:23][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (1 g, 2.76 mmol) in DMF (20 mL) was added sodium hydride (568 mg, 16.6 mmol, 70%) at 15° C., and followed by addition of 1-(bromomethyl)-4-methoxybenzene (2.22 g, 11.0 mmol). The resulting solution was stirred for 3 h at room temperature, quenched by addition of cold water (50 mL), and extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by silica gel column, eluted with 10-25% ethyl acetate in petroleum ether to give compound 9 as a yellow oil (1.2 g, 64%). (ES, m/z): [M+H]+ 603.1; 1H NMR (300 MHz, CDCl3) δ 7.22-7.35 (m, 4H), 6.84-6.92 (m, 4H), 6.27-6.29 (d, J=6.6 Hz, 1H), 4.60-4.76 (m, 4H), 4.36-4.43 (m, 2H), 4.10-4.17 (m, 2H), 3.81 (s, 6H), 3.72 (m, 1H), 3.61 (m, 1H), 2.99 (s, 6H), 0.83 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].S(Cl)([Cl:19])(=O)=O.O>C(Cl)Cl>[C:1]([N:5]1[CH2:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[S:8][CH:7]([Cl:19])[CH2:6]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: C=CC(=O)N1CCSc2ccccc2C1
Solvent: ClCCl
Solvent: O
Product: C=CC(=O)N1Cc2ccccc2SC(Cl)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
4-Acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (10 g) was dissolved in methylene chloride (150 ml) and sulfuryl chloride (9.3 g) was added thereto under ice cooling and agitated at 0° C. for 1 hour. To the reaction mixture water was added and extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and thereafter the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (70 parts)+ethyl acetate (30 parts) to give 4-acryloyl-2-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (10.5 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][CH:7]=[CH:6]2
Reactant: Fc1cc2cc[nH]c2cc1Br
Reactant: OB(O)c1ccccc1
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
Solvent: O
Product: Fc1cc2cc[nH]c2cc1-c1ccccc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A mixture of 6-bromo-5-fluoro-1H-indole (0.214 g, 1 mmol), phenylboronic acid (0.171 g, 1.4 mmol), sodium carbonate (1.06 g, 10 mmol), Pd(PPh3)4 (0.116 g, 0.1 mmol), 1,2-dimethoxyethane (5 mL) and water (5 mL) was stirred under nitrogen at 85° C. for 18 h. The mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-50% Et2O in petrol) gave 5-fluoro-6-phenyl-1H-indole (0.202 g, 95%) as a pale green solid. MS: [M+H]+=212. A solution of borane in THF (1 M, 1.42 mL) was added to 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.95 mmol) under nitrogen with external cooling using an ice-MeOH bath. The resulting mixture was stirred at 0° C. for 0.5 h, then TFA was added dropwise over 0.1 h. The mixture was stirred at 0° C. for 1 h then a solution of sodium hydroxide (0.8 g, 20 mmol) and water (5 mL) was added dropwise over 0.1 h. The resulting mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in petrol) gave the title compound (0.17 g, 85%) as an oil. MS: [M+H]+=214.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:41]=[CH:42][C:34]([N:28]6[CH2:29][CH2:30][O:31][CH2:32][CH2:33]6)=[N:35][CH:36]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(N2CCOCC2)nc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound, white solid (108 mg, 83%), MS (ISP) m/z=521.5 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 6-morpholin-4-yl-nicotinic acid.