Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[N:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[N:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Cc1cnc(Cl)nc1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
A solution of the compound (556 mg, 1.0 mmol) obtained in Example 16-5), 2-chloro-5-methylpyrimidine (193 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (298 mg, 57%) as a brown oily substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([C:20](=[O:40])[C@@H:21]([NH:23][C@H:24]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:22])[C:9]1=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:20](=[O:40])[C@@H:21]([NH:23][C@H:24]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:22])[C:9]1=[O:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)CC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O)C(=O)OCc1ccccc1
Yield: 92.5 %

Procedure:
1.2 g of tert.-butyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-4-methyl-n-pentyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 30 ml of a 13% hydrogen chloride-dioxane solution are treated in the same manner as described in Example 10-(3), whereby 1.0 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-4-methyl-n-pentyl)amino]-propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless viscous oil. This oil (1.0 g) and 50 mg of palladium black are treated in the same manner as described in Example 10-(5), whereby 0.75 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-4-methyl-n-pentyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. Yield: 84.3%
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:25](I)[CH3:26].[H-].[Na+].O>CN(C=O)C>[C:21]([O:20][C:18]([N:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[CH2:25][CH3:26])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1CCNCC1
Reaction time: 16 h
Yield: 126.1 %

Procedure:
To a solution of 476 mg (1.42 mmol) of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidine from Step B and 0.24 mL (2.8 mmol) of ethyl iodide in 10 mL of DMF was added 85 mg (2.1 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred for 16 h and was then poured into water and extracted three times with ether. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 15% ethyl acetate in hexanes to afford 409 mg of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]2[C:12](=[O:13])[O:11][C:9](=[O:10])[CH:5]2[CH2:6][C:7]=1[CH3:8]>[Pt](=O)=O.O1CCCC1>[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][C:5]2[C:9]([O:11][C:12](=[O:13])[C:4]=2[CH2:3]1)=[O:10]
Reactant: CC1=C(C)CC2C(=O)OC(=O)C2C1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CC1CC2=C(CC1C)C(=O)OC2=O
Reaction time: 8 h

Procedure:
A mixture of 4,5-dimethyl-4-cyclohexene-1,2-dicarboxylic anhydride (10 g; 0.0555 mol), platinum dioxide (150 mg) and tetrahydrofuran (100 ml) was hydrogenated at room temperature for 8 hours. Precipitates were removed by filtration, and the filtrate was evaporated under reduced pressure to give 4,5-dimethylcyclohexene-1,2-dicarboxylic anhydride. IR νmaxFilm (cm-1): 1860, 1760.
Reaction SMILES: [CH3:1][C:2]1[N:3](C(OCC(C)C)=O)[C:4]2[C:5]([N:21]=1)=[N:6][CH:7]=[C:8]([C:10]1[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][NH:16][CH2:15][C:14]=3[CH:20]=1)[CH:9]=2.Cl[C:30]1[C:35]([CH3:36])=[C:34]([CH2:37][CH3:38])[N:33]=[C:32]([CH2:39][N:40]([CH3:42])[CH3:41])[N:31]=1>>[CH2:37]([C:34]1[C:35]([CH3:36])=[C:30]([N:16]2[CH2:15][C:14]3[CH:20]=[C:10]([C:8]4[CH:9]=[C:4]5[N:3]=[C:2]([CH3:1])[NH:21][C:5]5=[N:6][CH:7]=4)[CH:11]=[CH:12][C:13]=3[O:19][CH2:18][CH2:17]2)[N:31]=[C:32]([CH2:39][N:40]([CH3:42])[CH3:41])[N:33]=1)[CH3:38]
Reactant: CCc1nc(CN(C)C)nc(Cl)c1C
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CNCCO4)cc2n1C(=O)OCC(C)C
Product: CCc1nc(CN(C)C)nc(N2CCOc3ccc(-c4cnc5[nH]c(C)nc5c4)cc3C2)c1C

Procedure:
Prepared according to the method of example 6 by using 2-methylpropyl 2-methyl-6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-imidazo[4,5-b]pyridine-1-carboxylate and 1-(4-chloro-6-ethyl-5-methylpyrimidin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (br s, 1H), 8.03 (br s, 1H), 7.70 (d, 1H), 7.52 (dd, 1H), 7.03 (d, 1H), 4.61 (s, 2H), 4.33-4.28 (m, 2H), 3.84-3.79 (m, 2H), 3.36 (s, 2H), 2.63 (q, 2H), 2.53 (d, 3H), 2.20 (s, 3H), 2.13 (s, 6H), 1.89 (s, 3H), 1.14 (t, 3H); MS (EI) for C26H31N7O: 458 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=1[O:8]CC1C=CC=CC=1>CCOC(C)=O.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=1[OH:8]
Reactant: CCOC(=O)/C=C/c1cc(Cl)c(OCc2ccccc2)c(OC)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(Cl)c(O)c(OC)c1
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a stirring solution of ethyl (2E)-3-{3-chloro-5-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (441 mg, 1.27 mmol) in EtOAc (9 mL) under nitrogen at ambient temperature was added PtO2 (20 wt %, 88 mg) and the mixture stirred under an atmosphere of hydrogen for 18 h. The resulting mixture was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with EtOAc. The filtrate was then reduced and purified further by SPE (silica, 10 g cartridge) eluting with cyclohexane:EtOAc (gradient 20:1 to 3:1) to give the title compound (287 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:11][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1.O.C[O-].[Na+]>CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C@H:8]1[CH2:9][C@H:10]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:11]1
Reactant: COC(=O)c1ccc2nc([C@H]3C[C@H](N4CCCC[C@@H]4C)C3)sc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@H]1CCCCN1[C@H]1C[C@H](c2nc3ccc(C(=O)O)cc3s2)C1
Temperature: 23 °C
Reaction time: 24 h

Procedure:
Methyl 2-{trans-3-[(S)-2-methylpiperidin-1-yl]cyclobutyl}-1,3-benzothiazole-6-carboxylate (Example 143A, 2.0 g, 5.8 mmol) was dissolved in methanol (600 mL), followed by H2O (300 mg, 16.7 mmol) and sodium methoxide (1.4 g, 26 mmol) at 23° C. The reaction mixture was then allowed to stir at 23° C. for 1 day. Solvent and excess of water were removed. HCl (2N) was added to make the mixture slightly acidic (pH ˜5-6). Excess of water was removed. The solid was triturated with CH2Cl2/MeOH, and filtrated. The solvents of the filtrate were removed under vacuum. The residue was treated with CH2Cl2 and filtrated again. Removal of the solvent gave the desired product as an off-white solid (2.13 g, 100%). 1H NMR (300 MHz, CD3OD): δ=8.54 ppm (d, J=1.3 Hz, 1H), 8.11 (dd, J=8.9, 1.3 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 2.70-3.10 (m, 7H), 2.00 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.41 (d, J=6.8 Hz, 3H). MS (ESI, M+H+): 331.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Br-].[C:13]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:20][Zn+])([CH3:16])([CH3:15])[CH3:14].Cl>O1CCCC1.CC(OC)(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>[C:13]([C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[CH2:20][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(C[Zn+])cc(C(C)(C)C)c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Br-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of methyl 2-chloroisonicotinate (4 g, 23.31 mmol) and Pd(PPh3)4 (0.539 g, 0.47 mmol) in tetrahydrofuran (120 mL) under nitrogen in a dried flask was added a freshly prepared solution of (3,5-di-tert-butylbenzyl)zinc(II) bromide (11.08 g, 31.78 mmol) in tetrahydrofuran (46 mL). The resulting bright yellow solution was heated to 60° C. for 35 min, then stirred at room temperature for 1 h. The reaction was quenched by addition of methanol (50 mL). The solution was diluted with EtOAc and washed with NH4Cl. The organic layer was dried over MgSO4, filtered and evaporated to yield a brown oil. The crude was redissolved in MTBE (180 mL) and solids were filtered off. Hydrogen chloride (4 M in dioxane, 6.42 mL, 25.66 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 10 min. The solid was collected by filtration and washed with MTBE. Redissolved in MTBE/satd NaHCO3. The phases were separated, the organic phase dried over Na2SO4, filtered and evaporated to yield methyl 2-(3,5-di-tert-butylbenzyl)isonicotinate (7.132 g, 90%) as a brown oil. 1H NMR (600 MHz, cdcl3) δ 1.28 (s, 18H), 3.89 (s, 3H), 4.19 (s, 2H), 7.11 (d, 2H), 7.27 (t, 1H), 7.64 (dd, 1H), 7.71 (s, 1H), 8.68 (d, 1H). MS m/z 340 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:9]([C:12]1[C:20]2[O:19][N:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[C:16]=2[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH2:27][CH2:28]Br)[CH2:10][CH3:11]>>[CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:28][CH2:27][CH2:26][O:25][C:13]2[CH:14]=[CH:15][C:16]3[C:17]([C:21]([F:23])([F:24])[F:22])=[N:18][O:19][C:20]=3[C:12]=2[CH2:9][CH2:10][CH3:11])[C:3]1=[O:8]
Reactant: CN1CC(=O)NC1=O
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Product: CCCc1c(OCCCN2C(=O)CN(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
1-Methyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 1-methylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20]CC4C=CC=CC=4)=[C:16]([F:28])[CH:15]=3)=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:28])[CH:15]=3)=[CH:10][N:9]=[CH:8]2)=[CH:29][CH:30]=1
Reactant: O=c1c(-c2ccc(OCc3ccccc3)c(F)c2)cncn1Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(-c2ccc(O)c(F)c2)cncn1Cc1ccc(Cl)cc1
Yield: 75.6 %

Procedure:
In a small round bottom flask, a solution of 3-(4-chlorobenzyl)-5-(4-(benzyloxy)-3-fluorophenyl)pyrimidin-4(3H)-one (0.17 g, 0.40 mmol) was heated in trifluoroacetic acid (5 mL) for 4 hours. The solvent was evaporated and the residue was dried under vacuum to afford the title compound as a white colored solid (0.1 g, 75%). LRMS (APCI pos) m/e 331.0 (M+1).
Reaction SMILES: [Na+].[CH3:2][C:3]([CH3:10])([CH3:9])[C:4](=O)[C:5]([O-:7])=[O:6].Cl.[NH2:12][OH:13]>O>[CH3:2][C:3]([CH3:10])([CH3:9])[C:4](=[N:12][OH:13])[C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=NO)C(=O)O
Yield: 81.2 %

Procedure:
163 g (1 mole) 93.5% trimethylpyruvic acid sodium salt and 69.5 g (1 mole) hydroxylamine hydrochloride were dissolved at 40° C. in 450 ml water. The product crystallized out during slow cooling off under agitation. After 1.5 h agitation in an ice bath the crystals were filtered off, washed with 150 ml ice water and at first pre-dried in a vacuum at 60° C. and then post-dried in a vacuum desiccator over phosphorus pentoxide to constant weight. 117.8 g (yield 81%) trimethylpyruvic acid oxime in the form of colorless crystals were obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:27])[O:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:17][CH2:18][N:19]([C:23]([O:24][CH2:25][CH3:26])=[O:27])[CH2:20][CH2:21]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Yield: 94.3 %

Procedure:
A mixture of 33.0 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine, 74.9 g of ethyl chlorocarbonate and 170 ml of toluene was refluxed for 3.5 hrs. After cooling, the reaction mixture was washed with hydrochloric acid and water, and then dried and concentrated. The residue was solidified by treatment with n-hexane to give 37.4 g of pale yellow crystals, which were recrystallized from ethanol to give slightly yellow needles, mp 123°-124° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:61]=[CH:62][CH:63]=1)[CH2:46][N:47]1[CH:51]=[C:50]([C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([C:6]4[CH:7]=[CH:2][C:3]([CH:28]5[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:32][CH2:33]5)=[CH:4][CH:5]=4)[CH:9]=3)[N:14]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=2)[CH:49]=[N:48]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Reactant: COc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(Cn2cc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(2-fluoro-4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (intermediate 67B) (125 mg, 0.190 mmol) was coupled with 1-(3-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 64F) (90 mg, 0.285 mmol) using Pd(dppf)Cl2 (7 mg, 0.009 mol) and sodium carbonate (181 mg, 0.578 mmol) in toluene/ethanol/water (20/10/5 ml) to afford 121 mg (crude) of the titled compound. MS: m/z=718.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][NH:18][C@@H:8]([C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].[CH:23]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:23]1([CH2:27][N:18]2[CH2:17][CH2:16][C@@:14]34[C:15]5[C:2]([OH:1])=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Reactant: BrCC1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1O)[C@]13CCN(CC4CCC4)[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3

Procedure:
Prepared by reaction of 18a (3.70 g, 12.3 mmole) with cyclobutylmethyl bromide (2.24 g, 14.7 mmole) in the presence of NaHCO3 (2.00 g, 25 mmole) in DMF (50 ml) at 100° under argon for 6 hours to give, after processing in the usual manner, 4.50 g (99%) of 19a-CBM as a foam. NMR: δ 6.60; 2H, s (aromatic); 5.5, 1H, broad (hydroxyl), 4.24, 1H, d (H-5α, J=13 Hz); 3.76 (CH3O--), 0.86, 3H, d(7α-CH3, J=6.5 Hz).
Reaction SMILES: [CH3:1][Li].[CH3:3][C@@H:4]1[CH2:9][C:8](=[O:10])[CH:7]=[CH:6][O:5]1>C(OCC)C.[Cu]I>[CH3:3][C@@H:4]1[CH2:9][C:8](=[O:10])[CH2:7][C@@H:6]([CH3:1])[O:5]1
Reactant: [Li]C
Reactant: C[C@@H]1CC(=O)C=CO1
Agent: [Cu]I
Solvent: CCOCC
Product: C[C@@H]1CC(=O)C[C@@H](C)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Methyllithium in diethyl ether (1.6M, 218 mL, 349 mmol) was added in ˜10 mL portions over 20 min to a stirred slurry of copper(I) iodide (44.3 g, 233 mmol) in diethyl ether (350 mL) cooled to 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 30 min and then (R)-2-methyl-2H-pyran-4(3H)-one (13.5 g, 116 mmol) in diethyl ether (150 mL) was added dropwise over 30 min. The cold bath was removed and the reaction mixture was allowed to warm to rt and stirred for 3 h. The reaction mixture was slowly added (over ˜5 min) to a stirred solution of sat. NH4Cl (aq) (˜750 mL) and ice. Additional diethyl ether (˜500 mL) and water (˜150 mL) were added and the solution, which contained a grey precipitate, was stirred overnight. The layers were separated and the aqueous layer was extracted with diethyl ether (500 mL) and DCM (500 mL). The combined organic phase was dried (MgSO4), filtered and concentrated (the rotary evaporator bath temperature was held at or below ambient temperature) to an orange oil. The crude oil was purified with a Biotage® Horizon (240 g SiO2, 1-4% diethyl ether in DCM, column was pre-equilibrated with DCM) to yield (2R,6R)-2,6-dimethyldihydro-2H-pyran-4(3H)-one (13.4 g, 86% pure by 1H-NMR) as a light yellow oil. [Note: The material was carefully concentrated and contained 10% w/w DCM by 1H-NMR. 1H-NMR analysis also indicated that the material was contaminated with ˜2.5% TBDMSOH carried over from a previous reaction and 1.6% of (2R,6S)-2,6-dimethyldihydro-2H-pyran-4(3H)-one]. The analytical data of the product complied with the data reported in the literature, and the material was used without additional purification. 1H-NMR (400 MHz, CDCl3) δ 4.41-4.25 (m, 2H), 2.55 (ddd, J=14.1, 4.8, 1.4 Hz, 2H), 2.24 (ddd, J=14.1, 6.5, 1.5 Hz, 2H), 1.28 (d, J=6.5 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:37])[CH2:39][OH:40])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34])([O-:26])=[O:25]>C(Cl)Cl>[C:11]([O:10][C:8]([C@@H:3]([CH2:2][NH:1][S:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N+:24]([O-:26])=[O:25])(=[O:34])=[O:35])[C:4]([O:6][CH3:7])=[O:5])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)[C@H](CN)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a mixture of (S)-methyl 3-amino-2-(tert-butoxycarbonyl)propanoate ii (1.6 g, 7.3 mmoL) in DCM (50 mL) was added DIPEA (1.64 mL, 9.4 mmoL) and 2-nitrobenzene sulfonyl chloride (1.62 g, 7.3 mmoL). The mixture was stirred at rt for 2 h. It was then concentrated, dissolved in ethyl acetate, which was then washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. It was then filtered, concentrated to yield 2.9 g (98%) of (S)-methyl 2-(tert-butoxycarbonyl)-3-(2-nitrophenylsulfonamido)propanoate iii as a yellow foam. 1H NMR (CD3OD, 300 MHz) δ 1.41 (s, 9H), 3.36–3.51 (m, 2H), 3.71 (s, 3H), 4.22 (m, 1H), 7.80–7.90 (m, 3H), 8.07–8.10 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:14](N)([NH2:17])(=[O:16])=[O:15]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([NH2:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NS(N)(=O)=O
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
A mixture of 4-(4-chlorophenyl)piperazine (6.63 g, 33.7 mmol) and sulfamide (3.89 g, 40.5 mmol) in water (10 ml) was heated at 120° C. After 96 h, the reaction mixture was cooled to RT, diluted with ethyl acetate (100 ml). Water (100 ml) was added and the reaction mixture was stirred vigorously for several minutes. The solid was filtered to give [4-(4-chlorophenyl)-piperazine-1-sulfonyl]amine as a white powder (59%), mp 218.0-220.0° C.