Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C[N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:21][C:22]2[CH:23]=[N:24][C:25](OCC)=[CH:26]C=2)CC1.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=O)=[CH:36][CH:35]=1)[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC1C=C(C=CC=1NCC1C=CN=CC=1)C(N(CC)CC)=O>>[CH2:31]([O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][C:41]2[N:5]([CH2:6][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:9]3[CH:10]=[CH:11][C:12]([C:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[O:15])=[CH:13][C:8]=3[N:7]=2)=[CH:38][CH:39]=1)[CH3:32]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2CC2CC2)cn1
Agent: CCN(CC)C(=O)c1ccc(NCc2ccncc2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2Cc2ccncc2)cc1
Yield: 36 %

Procedure:
Following general 13B, (4-ethoxyphenyl)acetic acid (0.0364 g, 0.202 mmol), HATU (0.0768 g, 0.202 mmol), DIPEA (0.048 mL, 0.28 mmol), and 3-amino-N,N-diethyl-4-[(4-pyridinylmethyl)amino]benzamide (0.0548 g, 0.184 mmol) were combined. The crude product was purified by reverse phase MPLC (gradient 10–50% CH3CN in H2O) to provide the title compound (0.0459 g, 36%) as its TFA salt. This material was lyophilized from H2O/dioxane to produce a white solid. 1H-NMR (CD3OD): δ 8.60 (br s, 2H), 7.87 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.42 (d, J=5.6 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 6.71 (d, J=9.6 Hz, 2H), 6.06 (s, 2H), 4.54 (s, 2H), 3.93 (q, J=7.2 Hz, 2H), 3.59 (br s, 2H), 3.31 (br s, 2H), 1.35 (t, J=6.8 Hz, 3H), 1.38–1.04 (2×br s, 6H). MS (ESI) (M+H)+443. Anal. Calcd for C27H30N4O2.2.1 TFA. 0.8H2O: C, 53.81; H, 4.88; N, 8.04. Found: C, 53.74; H, 4.89; N, 8.07.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH2:9]O>>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=[CH:8]1
Reactant: OCCO
Reactant: Nc1ccccc1
Product: c1ccc2[nH]ccc2c1
Temperature: 350 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
93.1 g (1 mole) of aniline and 6.2 g (0.1 mole) of ethylene glycol as well as 3.0 g of the above catalyst were introduced into a stainless steel autoclave having an inner volume of 200 ml. The inside of the autoclave was purged with nitrogen gas and then hydrogen gas was fed to a gauge pressure of 10 kg/cm2. The reaction was conducted under stirring, at 350° C. for one hour. The resulting reaction mixture was analyzed by gas chromatography. Thus, indole was obtained in a yield of 62.3% based on ethylene glycol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.CO[C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:26]([CH2:28][C:29]2[CH:38]=[CH:37][C:32]3[O:33][CH2:34][CH2:35][O:36][C:31]=3[CH:30]=2)[CH3:27])[CH2:22][CH2:21]1)=O>>[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][N:26]([CH3:27])[C@H:23]3[CH2:24][CH2:25][C@H:20]([CH2:18][O:14][C:13]([C:7]4[CH:8]=[N:9][C:10]5[C:5]([CH:6]=4)=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=5)=[O:15])[CH2:21][CH2:22]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: COc1ccc2ncc(C(=O)O)cc2c1
Reactant: COC(=O)[C@H]1CC[C@H](N(C)Cc2ccc3c(c2)OCCO3)CC1
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](N(C)Cc4ccc5c(c4)OCCO5)CC3)cc2c1

Procedure:
The title compound is prepared as a yellow oil following Scheme 2 and in analogy to Example 28 using 6-methoxy-quinoline-3-carboxylic acid and trans-4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-cyclohexanecarboxylic acid methyl ester as starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1.[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: ClCCCCC1OCCO1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 2-(4-chlorobutyl)-1,3-dioxolane and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 375.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[CH:6]=[C:5]2[C:13]([O:15][CH3:16])=[O:14].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([N:24]1[CH:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:12])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1coc(=O)c2ccc(Br)cc12
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)c1cn(Cc2ccccc2)c(=O)c2ccc(Br)cc12

Procedure:
A mixture of the product of Example 37 step ii) (5 g) and benzylamine (3 mL) in methanol (20 mL) was heated at reflux for 40 hours. The reaction was concentrated to half volume, then treated with acetonitrile. The sub-title compound was collected by filtration, washing with acetonitrile (5.30 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=[CH:28][C:21]=34)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].[ClH:37]>C(Cl)Cl.O1CCOCC1>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2=[N:23][CH:24]=[CH:25][C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)=[C:21]2[CH:28]=[CH:27]1.[ClH:37]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (1.6 g) in methylene chloride (10 mL) was added a solution of 4.0 M of hydrogen chloride in dioxane (20 mL). The mixture was stirred at room temperature overnight. Then it was concentrated under reduced pressure to afford the desired compound as HCl salt (1.5 g). LCMS (M+H)+: m/z=409.2.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH3:31])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(Cl)Cl>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:26]=[CH:27][C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[CH3:31])=[CH:29][C:2]=1[NH:1][CH:41]1[CH2:42][CH2:43][O:38][CH2:39][CH2:40]1
Reactant: O=C1CCOCC1
Reactant: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(NC2CCOCC2)c1
Yield: 46.5 %

Procedure:
2-Amino-N-[5-(3,5-difluoro-benzyloxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide (150 mg, 0.29 mmol) in DCM (4 mL) was treated, at 4° C., under a nitrogen atmosphere, with tetrahydro-4H-pyran-4-one (0.34 mL, 0.37 mmol), TFA (0.23 mL, 2.95 mmol) and finally with tetramethylammonium triacetoxyborohydride ((204 mg, 0.74 mmol). After 1.5 hours DCM, was added (25 mL) and the organic layer was washed with water (25 mL), saturated NaHCO3 solution (25 mL) and brine. After drying over anhydrous sodium sulfate, removal of the solvent and purification of the crude over silica gel (DCM: 7N NH3 in MeOH 9:1), 80 mg of title compound were obtained in 46% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11](N)=[S:12]>COCCOC.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.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:11]([CH3:10])[S:12][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC(N)=S
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: Cc1nc2ccc(Br)cc2s1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 4-bromo-2-iodo-phenylamine (1.5 g, 5.0 mmol), thiacetamide (381 mg, 5.0), cupric oxide (280 mg, 3.5 mmol), dppf (56 mg, 0.10 mmol), Pd2(dba)3 (48 mg, 0.052 mmol) in DME was heated at 60° C. for 1 hour, cooled to room temperature, partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4) and concentrated. The concentrate was purified by flash chromatography on silica gel using 20% hexanes/methylene chloride to give 550 mg (40% yield) of the desired product. MS (ESI(+)) m/e 227.8, 229.8 (M+H)+.
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][C:15]1[C:20](Br)=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[C:26](=[O:27])[N:25]([CH3:28])[N:24]=[N:23]1>O>[CH3:14][C:15]1[C:20]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[C:26](=[O:27])[N:25]([CH3:28])[N:24]=[N:23]1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: Cc1c(Br)cccc1-n1nnn(C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1c(S[Si](C(C)C)(C(C)C)C(C)C)cccc1-n1nnn(C)c1=O
Temperature: 90 °C
Yield: 91.7 %

Procedure:
Under ice-cooling, to a mixture of triisopropylsilanethiol 4.99 g and tolune 30 ml was added 60% sodium hydride 0.63 g, and the resulting mixture was stirred for thirty minutes. To the reaction mixture was added 1-(2-methyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 10) 2.82 g and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct 0.856 g. The reaction mixture was heated to 90° C. and was stirred for four hours. After cooling the reaction mixture, thereto was added water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(2-methyl-3-triisopropylsilanylsulfanylphenyl)-4-methyl-1,4-dihydrotetrazole-5-one 3.64 g.
Reaction SMILES: C1(COC(=O)[NH:10][C@H:11]([CH3:20])[C:12](=[O:19])[NH:13][N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)C=CC=CC=1>[Pd].CO>[NH2:10][C@H:11]([CH3:20])[C:12]([NH:13][N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)=[O:19]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)Nn1cccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N)C(=O)Nn1cccc1
Yield: 77.1 %

Procedure:
The CBZ group of (R)-phenylmethyl-[1-methyl-2-oxo-2-(1H-pyrrol-1-ylamino)ethyl]carbamate (5.13 g) was cleaved in a minimal volume of methanol over 5% Pd-C (1.03 g) with H2 (g) (436 ml) under atmospheric conditions. The catalyst was removed by filtration through a pad of celite and the filter cake was washed with methanol. The combined filtrates were concentrated and the residue purified via flash column chromatography (silica gel, 30% EtOH/EtOAc), affording 2.11 g of the product as a oil which crystallized on standing, m.p. 63°-66° C.
Reaction SMILES: [C-]#[N:2].[Na+].N.[C:5]1([C:11]2[C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[N:15]3[C:23]([CH:26]=[O:27])=[N:24][N:25]=[C:14]3[CH2:13][N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl>C(O)(C)C.[O-2].[O-2].[Mn+4]>[C:5]1([C:11]2[C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[N:15]3[C:23]([C:26]([NH2:2])=[O:27])=[N:24][N:25]=[C:14]3[CH2:13][N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: [C-]#N
Agent: [Mn+4]
Agent: N
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: NC(=O)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.08 h

Procedure:
0.245 g (0.005 mole) of sodium cyanide is added at 0°, with stirring, to the saturated solution of ammonia in 15 ml of isopropanol. After 5 minutes, a solution of 0.322 g (0.001 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde in ca. 10 ml of isopropanol is added together with 0.87 g of manganese dioxide. After a further 10 minutes, another addition is made of 0.87 g (total 0.02 mole) of manganese dioxide, and the mixture stirred for 4 hours at 0°. After the addition of ca. 40 ml of methylene chloride, the reaction mixture is filtered and the filtrate concentrated by evaporation. Crystallisation of the residue from methanol/ethyl acetate/petroleum ether yields 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxamide, M.P. 285°-289°.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[N:29][N:30]([CH2:32][CH2:33][OH:34])[CH:31]=1>>[OH:34][CH2:33][CH2:32][N:30]1[CH:31]=[C:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH:28]=[N:29]1
Reactant: Nc1cnn(CCO)c1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)Nc3cnn(CCO)c3)ccc1OCC2

Procedure:
Following the procedure for 126, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-amino-1-(2-hydroxyethyl)pyrazole to give 125 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 8.50 (d, J=2.2 Hz, 1H); 8.38 (s, 1H); 8.10 (s, 1H); 7.96 (s, 1H); 7.78-7.73 (m, 1H); 7.56 (s, 1H); 7.22 (d, J=8.4 Hz, 1H); 6.81 (s, 1H); 5.60-5.47 (m, 1H); 4.57 (t, J=5.7 Hz, 2H); 4.23 (t, J=4.8 Hz, 2H); 4.01 (t, J=4.8 Hz, 2H); 3.20 (t, J=5.7 Hz, 2H); 1.57 (d, J=6.6 Hz, 6H). 1 Exchangeable proton not observed. LCMS: RT=9.27 min, M+H+=449
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][CH:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][CH:14]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Br)cncc3c2)cc1
Reactant: COc1ccccc1B(O)O
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1cncc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a microwave vial charged with (2-methoxyphenyl)boronic acid (25.6 mg, 0.168 mmol), 4-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (Intermediate PPPP) (75 mg, 0.153 mmol), and potassium phosphate tribasic (38.0 μl, 0.459 mmol) was added dioxane (613 μl) and water (204 μl). The mixture was purged with argon prior to the addition of 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (10.83 mg, 0.015 mmol). The mixture was irradiated at 100° C. in a microwave for 30 min. The organics were decanted, the aqueous rinsed with EtOAc and the organics combined and dried under reduced pressure. The crude material was dissolved in DCM (1.5 ml) and TFA (0.5 ml) was added and the mixture shaken at room temperature for 2 hrs. The resulting mixture was dried under reduced pressure and purified with a 25 g Interchim HP spherical silica column (Interchim, Mouintlucon, France) (15 μm) ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) with product eluting at 100% polar eluent to afford 4-(2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-7-sulfonamide (40 mg, 0.101 mmol, 65.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.87 (d, J=4.60 Hz, 1H) 7.08-7.16 (m, 1H) 7.22 (d, J=8.22 Hz, 1H) 7.25-7.35 (m, 2H) 7.48-7.55 (m, 1H) 7.61 (d, J=8.90 Hz, 1H) 8.00 (dd, J=8.85, 1.91 Hz, 1H) 8.48 (s, 1H) 8.71 (d, J=1.76 Hz, 1H) 9.55 (s, 1H) 12.87 (br. s., 1H). m/z (ESI) 398.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:15])[CH3:14].[ClH:16]>O1CCOCC1>[ClH:16].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:15][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=N)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A stirred mixture of 4-hydroxy-3-nitrobenzonitrile 33 (5.2 g, 32 mmol) in a solution of abs. ethanol (250 ml) and dioxane (40 ml) was cooled in an ice bath as dry HCl gas was bubbled through it for 1 hr. The mixture was stirred overnight at room temperature and the resulting precipitate was collected, washed with ether and dried to give 6.2 g (79%) of the imidate ester HCl 34. 1H NMR (600 MHz, DMSO-d6) δ 11.8 (br s, 1H), 8.64 (s, 1H), 8.21 (d, 1H, J=9 Hz), 7.38 (d, 1H, J=9 Hz), 4.57 (q, 2H, J=7.2 Hz), 1.47 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[CH:3]=1.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[C:4](=[O:16])[C:3]=1[F:18]
Reactant: COC(=O)c1c(Cl)cc(=O)n2c1CCCC2
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)c(F)c(=O)n2c1CCCC2
Yield: 45.3 %

Procedure:
Methyl 8-chloro-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7b, 1.23 g, 5.1 mmol, 1 eq) was dissolved in DMF (10 ml) at 88° C. Selectfluor (3.61 g, 10.2 mmol, 2 eq) in DMF (10 ml) was added drop wise and the mixture heated for 2 hours. After concentration in vacuo the residue was purified by flash chromatography using 20-70% EtOAc/Hexane as eluent to give the title compound as an off-white solid (600 mg, 45%). [M+H] calc'd for C11H11ClFNO3, 260. found, 260
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)=[C:11]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:10]=1)([CH3:8])[CH3:7])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:62][N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1>ClCCl>[CH3:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:11]1[CH:10]=[C:9]([C:6]([CH3:7])([CH3:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH:14]=[CH:13][C:12]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:66]2[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]2)=[O:23])=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)O)cc2)c(OCCCOC)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)(C)c1ccc(-c2ccc(C(=O)N3CCN(C)CC3)cc2)c(OCCCOC)c1
Reaction time: 18 h
Yield: 42.8 %

Procedure:
In a round bottom flask, under an atmosphere of argon, 4′-(3-ethoxy-1,1-dimethyl-3-oxopropyl)-2′-(3-methoxypropoxy)biphenyl-4-carboxylic acid (1.0 g, 2.4 mmol) was dissolved in dichloromethane (40 mL). EDCl (0.55 g, 2.9 mmol), HOBT (0.39 g, 2.9 mmol) and diisopropylethylamine (2.10 mL, 12.1 mmol) were added at room temperature. After consumption of all the acid, N-methylpiperazine (0.27 mL, 2.4 mmol) was added and the mixture was stirred for 18 hrs. The organic layer was washed twice with water. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane/ethanol, 95/5) to yield 0.51 g (43%) of the desired product as a yellow oil.
Reaction SMILES: C1(N(CCO)C(C2C(OCC3C=CC=CC=3)=C(O)N=C(CC3(N4C5=NC=CC=C5C=C4)CCCC3)N=2)=O)CC1.[Si]([O:47][CH2:48][CH2:49][N:50]([CH:83]1[CH2:86][O:85][CH2:84]1)[C:51]([C:53]1[C:58]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[C:57]([OH:67])[N:56]=[C:55]([CH2:68][C:69]2([N:74]3[C:78]4=[N:79][CH:80]=[CH:81][CH:82]=[C:77]4[CH:76]=[CH:75]3)[CH2:73][CH2:72][CH2:71][CH2:70]2)[N:54]=1)=[O:52])(C(C)(C)C)(C)C>>[OH:47][CH2:48][CH2:49][N:50]([CH:83]1[CH2:86][O:85][CH2:84]1)[C:51]([C:53]1[C:58]([O:59][CH2:60][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)=[C:57]([OH:67])[N:56]=[C:55]([CH2:68][C:69]2([N:74]3[C:78]4=[N:79][CH:80]=[CH:81][CH:82]=[C:77]4[CH:76]=[CH:75]3)[CH2:73][CH2:72][CH2:71][CH2:70]2)[N:54]=1)=[O:52]
Reactant: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1COC1
Agent: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Product: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (422) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (418) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-oxetan-3-yl-amide (421) (180 mg, 0.27 mmol) and was obtained as light brown sticky solid (220 mg, crude).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[CH3:19][S:20]([CH2:22][CH2:23][C:24]1[CH:29]=[C:28]([NH:30][C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:27]=[CH:26][C:25]=1[S:37](Cl)(=[O:39])=[O:38])=[O:21]>CC#N>[F:34][C:32]([F:33])([F:35])[C:31]([NH:30][C:28]1[CH:27]=[CH:26][C:25]([S:37](=[O:38])(=[O:39])[NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:9][O:8][B:7]([OH:10])[C:6]=3[CH:11]=2)=[C:24]([CH2:23][CH2:22][S:20]([CH3:19])=[O:21])[CH:29]=1)=[O:36]
Reactant: Nc1ccc2c(c1)B(O)OC2
Reactant: CS(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CS(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.59 g, 3.9 mmol) and N-methylmorpholine (2.53 g, 25 mmol) in MeCN (70 mL) was added 2-(2-(methylsulfinyl)ethyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (1 g, crude, 2.6 mmol) in MeCN (20 mL) at 0° C., then the solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, and ethyl acetate and water was added to the residue. The organic layer was dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 30%-60%, 25 min) to give 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-(2-(methylsulfinyl)ethyl)phenyl)acetamide (0.3 g, yield 32%).