Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]#[CH:29])[CH2:23][CH2:22]1.C(N(C(C)C)C(C)C)C>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.[Cu]I.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:29]#[C:28][CH2:27][N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[S:18][C:11]=12)[NH2:5]
Reactant: C#CCN1CCN(C)CC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 60 °C
Yield: 84.1 %

Procedure:
A round-bottomed flask was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 200 mg, 0.477 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A, 205.8 mg, 1.19 mmol), tetrakis(triphenylphosphine)palladium (0) (55.1 mg, 0.0477 mmol), copper(I) iodide (9.074 mg, 0.0477 mmol), N-ethyl-N-isopropylpropan-2-amine (2.49 ml, 14.3 mmol) and THF (25 mL). The reaction mixture was stirred at 60° C. until the starting material had been consumed (4 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (0.159 g, 84.2%). LRMS (APCI pos): m/e 397 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, 1H), 7.58 (s, 1H), 7.01 (t, 1H), 6.43-6.58 (m, 3H), 3.90 (br s, 2H), 3.61 (s, 2H), 2.48-2.83 (m, 8H), 2.38 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[O:12]1[CH2:17][CH2:16][CH:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.CN(C)C(=O)C>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)=[O:19])[N:10]=2)[N:7]=1
Reactant: O=C(Cl)C1CCOCC1
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-iodoimidazo[1,2-b]pyridazin-2-amine (550 mg, 2.11 mmol), tetrahydro-2H-pyran-4-carbonyl chloride (320 mg, 2.15 mmol) and N,N-dimethylacetamide (5.0 mL) was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the precipitated solid was collected by filtration, washed with water, and air-dried to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)tetrahydro-2H-pyran-4-carboxamide as a white powder.
Reaction SMILES: [OH-].[Na+].[C:3](Cl)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:26]=[CH:27]/[C:28]2[N:42]=[C:31]3[CH:32]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH2:33][CH2:34][CH2:35][N:30]3[N:29]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[CH:26]=[CH:27]/[C:28]2[N:42]=[C:31]3[CH:32]([CH:36]4[CH2:37][CH2:38][N:39]([C:4]5([CH:3]=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]5)[CH2:40][CH2:41]4)[CH2:33][CH2:34][CH2:35][N:30]3[N:29]=2)[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1
Reactant: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCNCC2)ccc1-n1cnc(C)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCN(C3(C=O)C=CC=CC3)CC2)ccc1-n1cnc(C)c1

Procedure:
A 1 N sodium hydroxide solution (0.5 ml) and benzoyl chloride (11 ul) were added to a solution of racemic 2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperidin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained in Examples 118 and 119 (20 mg) in methylene chloride (1 ml), and the reaction solution was stirred under ice-cooling for four hours. Methylene chloride was added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 19 mg of racemic 1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]phenylmethanone. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 50% ethanol-hexane) to obtain the title optically active compound with a retention time of 16 minutes and positive optical rotation (6.9 mg; 100% ee) and the title optically active compound with a retention time of 22 minutes and negative optical rotation (6.8 mg; >99% ee).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O1CCCC1.[CH3:14][NH2:15]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:15][CH3:14])[CH2:4][CH2:3]1
Reactant: CN
Reactant: CN1CCC(=O)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNC1CCN(C)CC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A mixture of 1-methyl-4-piperidone (20 g, 0.18 mol) in methanol:tetrahydrofuran (100 mL, 1:1) and methyl amine (2 M in tetrahydrofuran, 3 mole excess) was placed in a Parr shaker with 5% Pd/C and hydrogenated for two hours at 60 psi and 70° C. The catalyst was filtered and the filtrate concentrated on the rotary evaporator. The crude material was distilled at 44-45° C. at 0.3 mm Hg to give 20 g (87%) of 1-methyl-4-methylaminopiperidine. Anal. Calc'd for C7H16N2: C, 65.57; H, 12.58; N, 21.85. Found: C, 65.49; H, 12.44; N: 21,49.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=O)([O-:19])=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C.O>[N+:17]([C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH2:23][CH:24]2[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:9])[C:2]1=[O:1])([O-:19])=[O:18]
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Reactant: O=C(Nc1ccncc1)c1ccc[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1cccn(C2CCc3c2cccc3[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a mixture of 2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (8.0 g, 1.0 eq) in dry DMF (30 mL) was added 4-nitro-2,3-dihydro-1H-inden-1-one (1.2 eq) and PPh3 (3.0 eq), then added DIAD (3.0 eq) under N2 atmosphere. Then the mixture was stirred at room temperature overnight. At the end of reaction, water was added and extracted with ethyl acetate. The combined organic layer was washed with brine and dried over MgSO4, filtrated and evaporated to give the crude product, which was purified by Flash Column (PE:EtOAc=1:2), concentrated the crude product, and recrystallized by EtOAc to give 1-(4-nitro-2,3-dihydro-1H-inden-1-yl)-2-oxo-N-(pyridin-4-yl)-1,2-dihydropyridine-3-carboxamide (3.5 g, 21%). MS (ESI) 377.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.22 (s, 1H), 8.62 (m, 1H), 8.53 (m, 2H), 8.24 (m, 1H), 7.67 (m, 2H), 7.49 (m, 2H), 6.75 (m, 1H), 6.50 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 2.97 (m, 1H), 2.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][OH:23])=[O:9])([CH3:6])[CH3:5].[F:25][C:26]1[CH:27]=[C:28](O)[CH:29]=[C:30]([F:32])[CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][O:23][C:28]1[CH:27]=[C:26]([F:25])[CH:31]=[C:30]([F:32])[CH:29]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCO
Reactant: Oc1cc(F)cc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCOc1cc(F)cc(F)c1

Procedure:
To a solution of 67 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester and 29 mg 3,5-difluorophenol in 1 ml THF at 0° C. 58 mg triphenyl phosphine and 46 μl diisopropylazodicarboxylate were added. After 16 h at room temperature the reaction was concentrated in vacuo and after chromatography on silica (ethyl acetate/heptane) 80 mg 2-({1-[2-(3,5-difluoro-phenoxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]3[O:15][C:16](=[O:18])[CH:17]=[C:10]23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26]N1C(=O)CCC1=O>C(#N)C>[Cl:26][C:17]1[C:16](=[O:18])[O:15][CH:11]2[CH2:12][CH2:13][CH2:14][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1C=C2C(CCCN2Cc2ccc(Cl)nc2)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1OC2CCCN(Cc3ccc(Cl)nc3)C2=C1Cl
Reaction time: 1 h
Yield: 72.6 %

Procedure:
524 mg (1.98 mmol) of 4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one (1-2) are dissolved in 20 ml of acetonitrile, then 414 μl (2.97 mmol) of triethylamine and 317 mg (2.37 mmol) of N-chlorosuccinimide are added at room temperature. After one hour of stirring, a 159 mg (1.19 mmol) of N-chlorosuccinimide are added. After a further hour of stirring, the entire reaction mixture is concentrated under reduced pressure. The residue is taken up in dichloromethane, washed successively twice with 1N aqueous hydrochloric acid, twice with 1N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 430 mg (72% of theory) of 3-chloro-4-[(6-chloropyridin-3-yl)methyl]-5,6,7,7a-tetrahydrofuro[3,2-b]pyridin-2(4H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26]Br)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([C:20]2[S:21][C:22]([CH2:26][N:29]3[CH2:34][CH2:33][S:32][CH2:31][CH2:30]3)=[CH:23][C:24]=2[Cl:25])=[O:19])=[CH:4][CH:3]=1
Reactant: C1CSCCN1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CBr)cc1Cl
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Cl)ccc1NC(=O)c1sc(CN2CCSCC2)cc1Cl
Yield: 73.9 %

Procedure:
In a similar manner to that described in Paragraph A above, N-(4-chlorophenyl)-2-[((5-(bromomethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide (0.5 g, 1.0 mmol) was reacted with thiomorpholine (0.5 mL, 4.8 mmol). Purification by flash chromatography on silica gel afforded 0.4 g (73% yield) of N-(4-chlorophenyl)-2-[((5-((thiomorpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; as a pale yellow powder; NMR (CDCl3) 11.0 (s, 1), 9.0 (s, 1), 8.2 (d, 1), 7.8 (d, 2), 7.5 (d, 1), 7.4 (d, 2), 7.4 (s, 1), 7.2 (dd, 1), 3.7 (s, 2), 2.8 (m, 4), 2.7 (m, 4) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CO.Cl.[C:17](=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)cc(C(=O)O)c(Cl)c1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)c(C)c(N)c1Cl

Procedure:
30 g of 3-amino-2,5-dichloro-4-methylbenzoic acid are initially introduced into 140 ml of MeOH. HCl gas is now passed in for 20 minutes and the mixture is then boiled under reflux for a further 5 hours. After cooling, the mixture is poured into water and rendered alkaline with sodium carbonate. The ester which has precipitated is isolated and dried. Yield: 30.8 g, melting point: 53°-55°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][OH:14].[H][H]>[Ni].C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: O=[N+]([O-])c1ccc(C#CCO)c(Cl)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCO)c(Cl)c1
Reaction time: 12 h

Procedure:
A suspension of 1.25 g (6.808 mmol) 3-(2-chloro-4-nitro-phenyl)-prop-2-yn-1-ol and 1.00 g Raney nickel in 50 mL THF was hydrogenated for 12 h at RT and 25 psi hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated down i. vac.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH:6]([S:8]([CH:10]=[CH2:11])=[O:9])=[CH2:7]>O>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[CH2:11][CH2:10][S:8](=[O:9])[CH2:6][CH2:7]1
Reactant: C=CS(=O)C=C
Reactant: NCCCO
Solvent: O
Product: O=S1CCN(CCCO)CC1
Yield: 95.9 %

Procedure:
Step 1. To a solution of 3-amino-1-propanol (1.33 g, 17.64 mmol) in water (30 ml) was added divinylsulfoxide (2.0 g, 19.6 mmol). After the reaction mixture was refluxed for 0.5 h, it was concentrated and dried in vacuo at 50° C. to afford 4-(3-hydroxypropyl)thiomorpholine 1-oxide (3.0 g, 96%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.71-1.85 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 2.75-2.99 (m, 6H), 3.01-3.27 (m, 2H), 3.73 (t, J=5.9 Hz, 2H), 4.22 (brs, 1H). Step 2. To a solution of OZ288 (0.50 g, 1.4 mmol), 4-(3-hydroxypropyl)thiomorpholine 1-oxide (0.50 g, 2.8 mmol), triphenylphosphine (0.74 g, 2.8 mmol), and triethylamine (0.4 ml, 2.8 mmol) in dry THF (50 ml) at 0° C. was added dropwise a solution of DIAD (0.57 g, 2.8 mmol) in THF (10 ml). After stirring at rt overnight, the solvent was removed in vacuo. The residue was dissolved in EtOAc (50 ml) and washed with water (3×50 ml), dried over MgSO4, and concentrated. The residue was purified by chromatography (silica gel, 50% EtOH in EtOAc) to afford OZ466 free base (0.47 g, 65%) as a colorless solid. To a solution of OZ466 free base (0.47 g, 0.91 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.09 g, 0.91 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ466 (0.50 g, 90%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.45-1.98 (m, 22H), 2.12-2.21 (m, 2H), 2.39 (s, 3H), 2.51-2.61 (m, 1H), 3.04-3.85 (m, 10H), 4.02 (t, J=6.1 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 9.78 (brs, 1H); 13C NMR (125.7 MHz, DMSO-d6) δ 23.50, 26.01, 26.42, 31.49, 34.29, 34.45, 35.98, 36.28, 40.89, 42.13, 54.50, 64.91, 108.32, 110.73, 114.63, 127.65, 138.48, 156.68. Anal. Calcd for C30H45NO8S2: C, 58.89; H, 7.41; N, 2.29. Found: C, 57.47; H, 6.94; N, 2.23.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([NH:15][CH2:16][CH2:17][CH3:18])=[N:13][CH:14]=1.[OH-].[K+].I[CH2:24][CH2:25][CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([N:15]([CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH3:18])=[N:13][CH:14]=1
Reactant: CCCI
Reactant: CCCNc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)c1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
To a solution containing 0.2 g (0.74 mmol) of 5-(2,4-dimethylphenyl)-3-methyl-2-propylaminopyrimidin-4(3H)-one in 5 ml of tetrahydrofuran under a nitrogen atmosphere was added 0.12 g (2.2 mmol) of potassium hydroxide followed by 0.38 g (2.2 mmol) of 1-iodopropane. The reaction was allowed to stir at room temperature for 12 h, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 30% ethyl acetate/dichloromethane gave 0.15 g (65%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[OH-].[K+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13]([CH2:12][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])=[O:14])[CH3:17]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cn1cc(Cl)cnc1=O
Yield: 39 %

Procedure:
5-Chloropyrimid-2-one (0.02 mol) was added to a stirred solution of KOH (0.02 mol) in ethanol (100 ml) followed by addition of ethyl bromoacetate (0.023 mol). The reaction mixture was heated under reflux for 4 h. The reaction mixture was then evaporated to dryness at reduced pressure and the residue was extracted with chloroform (150 ml). The chloroform extract, after filtration, was washed with aqueous 0.5 N NaOH (2×3 ml) and water (3 ml). Evaporation of the dried (MgSO4) solution left the product which was recrystallized from acetone; yield 39%, m.p. 175°-177° C. (Found: C 44.65; H, 4.17. Calc. for C8H9ClN2O3 : C 44.36; H, 4.19).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[NH2:20][CH2:21][C@@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[Si:24]([O:23][C@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:21][NH:20][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A mixture of Intermediate 26 (0.33 g, 1.0 mmol) and Intermediate 2 (0.40 g, 1.2 mmol) in DMF (5 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.25 mL, 1.5 mmol) and catalytic potassium iodide. The mixture was heated overnight in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 12 g Isco RediSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound (0.53 g, 90%). ES/MS calcd. for C30H37F3N3O4Si+588.3. found m/z=588.4 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:56])([F:55])[CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:52]2[CH2:53][CH2:54][CH:49]([C:48]([F:56])([F:55])[F:47])[CH2:50][CH2:51]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: FC(F)(F)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(C(F)(F)F)CC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-trifluoromethylpiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].Cl[C:7]1(Cl)[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][S:2]([N:5]=[C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: ClC1(Cl)Oc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CS(=O)(=O)N=c1oc2ccccc2o1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
53.4 g of methanesulfonamide and 89.4 g of 2,2-dichloro-1,3-benzodioxole were heated under reflux with 400 ml of anhydrous ethyl acetate for 7 hours. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 200 ml of benzene, and the mixture was refluxed for 10 minutes and then cooled slowly to room temperature with stirring. The crystals deposited were collected by filtration and washed with benzene, water and 2-propanol in this order to obtain 83 g (yield: 83%) of 2-methanesulfonylimino-1,3-benzodioxole.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:39](OCC)=[O:40].C(N(C(C)C)CC)(C)C>CO>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH:39]=[O:40])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reactant: CCOC=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 48 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in methanol (0.5 mL) was added ethyl formate (3 mL) followed by diisopropylethylamine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 48° C. for 18 h and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-formyl -3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (0.092 g, 58%). MS: 569.1 (M+H)+