Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:41])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO>[CH3:17][C:16]([CH3:19])([CH3:18])[C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)=[CH:25]1)[CH2:10][C:9]([OH:41])=[O:8])[C:20](=[O:23])[NH:21][CH3:22]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(C)(C)C
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1)C(C)(C)C
Yield: 32 %

Procedure:
According to the procedure described in Example 1(a), N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed in MeOH after 20 hours. Purification via flash column chromatography with 1% HOAc/10% MeOH/CHCl3 as eluant and azeotrope with n-heptane furnished 24 mg(32%) of N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)-3(R)-[3-(4-(pyridin-4-yl)phenyl)-1H-pyrrol-1-yl]succinamic acid as yellow crystals. 1H NMR (CD3OD): δ 8.54 (d, 2H, J=5.6 Hz), 7.99 (bd, 1H, J=4.4 Hz), 7.80-7.59 (m, 6H), 7.34 (t, 1H, J=1.9 Hz), 6.92 (t, 1H, J=2.5 Hz), 6.55 (dd, 1H, J=1.9, 2.8 Hz), 5.28 (t, 1H, J=7.2 Hz), 4.17 (s, 1H), 3.23 (dd, 1H, J=7.5, 16.7 Hz), 3.01(dd, 1H, J=7.2, 16.7 Hz), 2.66 (d, 3H, J=3.5 Hz), 0.95 (s, 9H). IR(KBr): 3422, 1654, 1598, 1562, 1535 cm−1. HRFABMS: Calculated for C26H31N4O4 (M+H+):463.2345. Found: 463.2356. Anal. Calculated for C26H30N4O4.1.15H2O.0.1CHCl3: C, 63.30; H, 6.59; N, 11.31. Found: C, 6.58; N, 11.08.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:29])([F:28])[C:10]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+].ClC1[N:42]=[CH:41][C:40]([B:43]([OH:45])[OH:44])=[CH:39][N:38]=1>>[CH2:26]([O:25][C:23]([C:10]1([C:9]([F:8])([F:28])[F:29])[CH2:11][CH2:12][N:13]([C:16]2[N:42]=[CH:41][C:40]([B:43]([OH:45])[OH:44])=[CH:39][N:38]=2)[CH2:14][CH2:15]1)=[O:24])[CH3:27]
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: CCOC(=O)C1(C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(F)(F)F)CCN(c2ncc(B(O)O)cn2)CC1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
TFA (5 mL) was added to 1-tert-butyl 4-ethyl 4-(trifluoromethyl)piperidine-1,4-dicarboxylate (0.42 g, 1.29 mmol). The mixture was stirred for 30 minutes, then rotary evaporated to dryness and left on a high vacuum line for 1 h. The residual syrup was dissolved in ethanol (4 mL), anhydrous sodium carbonate (0.35 g, 3.3 mmol) was added, and the mixture was stirred for 10 minutes. (2-Chloropyrimidin-5-yl)boronic acid (0.23 g, 1.4 mmol) was added and the reaction mixture was stirred at 60° C. for 6 h. The mixture was filtered through celite and concentrated to give the title compound (0.4 g, 89%) as an off-white foam, which was used without further purification. LCMS (pH 10) MH+ 348, RT 1.31 minutes.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:16]4[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19][C:17]=4[N:18]=3)=[C:9]([F:35])[CH:8]=2)C[CH2:2]1.C(NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(F)C=1)=O)C>>[CH2:1]([NH:4][C:5](=[O:36])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:16]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:19][C:17]=3[N:18]=2)=[C:9]([F:35])[CH:8]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Agent: CCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)OC(C)(C)C)C3)c(F)c1

Procedure:
Method as described for tert-Butyl 2-(4-(3-cyclopropylureido)-2-fluorophenyl)-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (example 143) using 1-ethyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 28).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][N:19]3[CH2:26][CH:27]([NH2:30])[CH2:28][CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](O)=[O:35].CCN=C=NCCCN(C)C>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[CH2:20][N:19]3[CH2:26][CH:27]([NH:30][C:34]([C:33]3[C:32]([CH3:31])=[N:40][CH:39]=[CH:38][CH:37]=3)=[O:35])[CH2:28][CH3:29])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CCC(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCC(CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12)NC(=O)c1cccnc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
To a solution of 4-(2-amino-butyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (100 mg, 0.233 mmol) in pyridine (4 mL) was added 2-methyl-nicotinic acid (38.4 mg, 0.280 mmol) and EDCI (71.5 mg, 0.373 mmol). The solution was stirred overnight at room temperature, then diluted with water (5 mL). The mixture was poured into a separatory funnel and diluted further with water (20 mL). The mixture was extracted with EtOAc (2×20 mL), then the combined organic layers were washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield a yellow-brown oil which was purified via column chromatography. The resulting yellow solid was dissolved in methanol (2 mL) and HCl in Et2O (2M, 2 mL) was added. The mixture was stirred for 5 minutes, then concentrated to yield 103 mg of 6,6-dimethyl-4-{2-[(2-methyl-pyridine-3-carbonyl)-amino]-butyl}-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide (71% yield).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]5([C:35]([O:37]C(C)C)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[C:41]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]5([C:35]([OH:37])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)OC(=O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(c2cn3nc(NCCCN4CCC(OC(c5ccccc5)c5ccccc5)CC4)ccc3n2)CCCC1
Yield: 70.5 %

Procedure:
598 mg of isopropyl 1-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]cyclopentanecarboxylate dihydrochloride was dissolved in 3 ml of ethanol; 2.24 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 7 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water, washed with ethyl acetate and adjusted to pH 4.5 by the addition of 1 N hydrochloric acid. The mixture was saturated with sodium chloride and extracted with ethyl acetate-tetrahydrofuran (1:2); the extract was dried over magnesium sulfate and concentrated under reduced pressure, powdered by the addition of ethyl acetate-ethyl ether (1:1), washed with ethyl ether and dried to yield 349 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]3[CH2:37][CH2:36]3)[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]1([C:31]2[CH:30]=[C:29]([C:25]3[CH:24]=[C:23]([C:21]4[CH2:20][C:19](=[O:38])[NH:18][C:9]5[CH:10]=[C:11]([C:14]([F:15])([F:17])[F:16])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:28]=[CH:27][CH:26]=3)[CH:34]=[CH:33][N:32]=2)[CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CC3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(C4CC4)c3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M266) (274 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (168 mg, 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][CH:17]=[CH2:18])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:2].C([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=1)(=O)C.C(N(CC)CC)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16]/[CH:17]=[CH:18]/[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([OH:23])[CH:25]=1)[S:12]([CH3:15])(=[O:13])=[O:14])[CH3:2]
Reactant: CC(=O)Oc1cccc(I)c1
Reactant: C=CCN(CCCCCCC(=O)OCC)S(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCCN(C/C=C/c1cccc(O)c1)S(C)(=O)=O
Temperature: 80 °C
Yield: 28.8 %

Procedure:
To a solution of 7-(allyl-methanesulfonyl-amino)-heptanoic acid ethyl ester (250 mg, 0.86 mmol), 1-acetyloxy-3-iodo-benzene (225 mg, 0.86 mmol), and triethylamine (139 mL, 1 mmol) in DMF (3 mL) was added palladium acetate (25 mg). The reaction was heated to 80° C. under nitrogen for 24 h. The mixture was cooled to room temperature and aqueous sodium thiosulfate and CH2Cl2 were added. The aqueous solution was extracted with CH2Cl2 (2×) and the combined organic layers were washed with water (1×) and brine (1×). The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by radial chromatography (hexanes to 25% EtOAc/hexanes) to afford the title compound of Step A (95 mg). 1H NMR (CDCl3 400 MHz) δ 6.88–7.34 (m, 4H), 6.53–6.60 (m, 1H), 6.13–6.20 (m, 1H), 4.10 (q, 2H), 3.95 (d, 2H), 3.17–3.21 (m, 2H), 2.85 (s, 3H), 2.24–2.31 (m, 2H), 2.31 (s, 3H), 1.56–1.62 (m, 4H), 1.27–1.33 (m, 4H), 1.23 (t, 3H).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(O)[CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>C(Cl)Cl>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C
Yield: 71.1 %

Procedure:
Compound 9 (2.0 g, 6.41 mmol., 1.0 eq.), K2CO3 (1.77 g, 12.82 mmol., 2.0 eq.), halide (5.28 g, 32.05 mmol., 5.0 eq.) and DMF (25.0 mL) were combined and heated to 100° C. overnight. The crude reaction mixture was mixed with H2O (30 mL) and CH2Cl2 (35 mL). The organic phase was separated and the aqueous phase was washed with CH2Cl2 (2×25 mL). The combined organic phase was washed with brine and concentrated. The crude material was purified on a silica column to give compound 10 (1.2 g). The structure was confirmed by 1H NMR and LC/MS.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:10].C[C:27]([N:29](C)C)=O>C(OCC)(=O)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-]#N.[Zn+2].[C-]#N>[C:27]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C@H:12]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:10])#[N:29]
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2Br)[C@H](c2ccccc2)O1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2C#N)[C@H](c2ccccc2)O1
Temperature: 80 °C

Procedure:
A mixture of the product from Example 19 (355 mg, 0.88 mmol), tetrakis(triphenylphosphine)palladium(0) (102 mg, 10 mol %) and zinc cyanide (103 mg, 0.88 mmol) in dimethylacetamide (8.0 mL) was heated at 80° C. for 8 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 mL). The organic layer was washed with water, separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to afford 309 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C@@H:11]([NH:10][S:7]([C:5]2[S:6][C:2]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[C:12]([OH:14])=[O:13])=[CH:17]1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc(Br)s1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1ccc(S(=O)(=O)N[C@H](Cc2c[nH]c3ccccc23)C(=O)O)s1
Temperature: 50 °C
Yield: 70.9 %

Procedure:
In a round bottom flask was added crude compound (R)-2-(5-Bromo-thiophene-2-sulfonylamino)-3-(1H-indol-3-yl)-propionic acid product (3) (0.25 g, 0.584 mmol) (synthesized via Example 1, Step A), commercially available ethynyltrimethylsilane (0.17 g, 1.73 mmol), PdCl2P(PPh3)2 (0.041 g, 0.061 mmol), copper(I)iodide (0.006 g, 0.0315 mmol), and triethylamine (0.177 g, 1.75 mmol) dissolved in dry DMF (3 mL) under an atmosphere of nitrogen and mixture heated at 50° C. for two hours. The reaction mixture was then diluted with ethyl acetate and washed with a solution composed of NaCl/NaHCO3/(NH4)2CO3/water (1:1:1:1) (×3), water, brine, and dried (Na2SO4) to give the desired crude (R)-3-(1H-Indol-3-yl)-2-(5-trimethylsilanylethynyl-thiophene-2-sulfonylamino)-propionic acid 115 (185 mg, 71%). LC-MS (ES+) 447; (ES−) 445.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.Cl.[CH3:25][C:26]([NH2:35])([CH3:34])[CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[CH3:34][C:26]([NH:35][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:25])[CH2:27][N:28]1[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: CC(C)(N)CN1CCOCC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CN1CCOCC1
Temperature: 160 °C
Yield: 29 %

Procedure:
A mixture of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (40 mg, 0.13 mmol), 2-methyl-1-morpholinopropan-2-amine dihydrochloride [prepared according to the procedures reported in US 20060035903 A1 (2006)] (62 mg, 0.27 mmol) and DIPEA (0.14 mL, 0.81 mmol) in DMSO (2 mL) in a sealed glass tube was heated at 160° C. in a microwave for 45 min. It was diluted with 50 mL of EtOAc, washed with 5 mL of sat. NaHCO3 followed by 5 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (3% MeOH in DCM followed by 3-10% of 2 M NH3 in MeOH in DCM) to provide the title compound (17 mg, 29% yield) as a yellow off white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.85 (1H, br.), 7.79 (1H, dd, J=7.4, 1.2 Hz), 7.60 (1H, dd, J=8.0, 1.2 Hz), 7.35 (1H, t, J=7.7 Hz), 7.02 (1H, s), 6.96 (1H, s), 6.32 (1H, s), 3.60 (4H, m), 3.44 (2H, td, J=6.9, 2.2 Hz), 3.30 (4H, m), 2.86 (2H, t, J=6.8 Hz), 2.70 (2H, s), 2.58 (3H, s), 1.55 (6H, s). m/z (ESI, +ve) 435.0 (M+H)+.
Reaction SMILES: CO.[CH2:3](C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1SCCCC)[C:4]1C=CC=CC=1.[CH2:28]([C:35]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C>[CH2:28]([C:35]1[C:43]([S:44](=[O:47])(=[O:46])[NH2:45])=[CH:42][C:38]([C:39]([O:41][CH2:3][CH3:4])=[O:40])=[CH:37][C:36]=1[S:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cc1ccccc1
Solvent: CCO
Solvent: CO
Product: CCOC(=O)c1cc(SCc2ccccc2)c(Cc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 124, methanol with ethanol and 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid with 4-benzyl-3-benzylthio-5-sulfamylbenzoic acid and following the procedure described, ethyl 4-benzyl-3-benzylthio-5-sulfamylbenzoate is obtained with a melting point of 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH3:12])=[C:9]([Br:13])[CH:8]=[C:7]([O:14]C)[C:5]=2[N:6]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[C:10]([O:11][CH3:12])=[C:9]([Br:13])[CH:8]=[C:7]([OH:14])[C:5]=2[N:6]=1
Reactant: COc1cc(Br)c(OC)c2sc(N)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1c(Br)cc(O)c2nc(N)sc12

Procedure:
To a solution of 1 mmol of 2-Amino-4,7-dimethoxy-6-bromo benzothiazole in CH2Cl2 was added 2.2 mmol of BBr3 in CH2Cl2 at 0° C. for 16 h. Aqueous work-up and chromatography gave 2-amino-4-hydroxy-6-bromo-7-methoxy benzothiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH2:15][C:16]([NH2:18])=[O:17].C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]1[C:16](=[O:17])[NH:18][C:21](=[O:20])[C:22]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CN1CCN(c2ccc(N)c(CC(N)=O)c2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[2-amino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (124 mg, 0.50 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (4.0 mL) is added a solution of 1.0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at 0° C. under argon. After stirring for 30 min at 0° C. and 30 min at RT, TLC indicates the complete consumption of the acetamide. The dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat., aqueous NH4Cl solution. The aqueous layer is extracted with EtOAc (2×25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2SO4, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/AcOH/H2O 5.5:1:1) to afford the title compound as its water soluble acetate salt. Red solid. 1H NMR (DMSO-d6, 400 MHz): δ 1.70 (s, 9H, CH3COO−), 2.25 (s, 3H), 2.22-2.38 (m, 4H), 2.78-2.84 (m, 4H), 6.51 (d, J=8.7 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.64-6.68 (m, 2H), 6.77 (dd, J=8.7 Hz, J=2.8 Hz, 1H), 6.97-7.02 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 11.91 (bs, 1H). ES+-MS: 402 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:38][OH:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:41][C:42]#[N:43]>CN(C)C=O>[C:7]([NH:26][C:27]1[S:28][CH:29]=[C:30]([C:32](=[N:38][O:39][CH2:41][C:42]#[N:43])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:31]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
Potassium carbonate (4.84 g.) was added to a stirred solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.) in N,N-dimethylformamide (22.0 ml.). Chloroacetonitrile (2.64 g.) was added dropwise to the solution under nitrogen atmosphere and stirred at room temperature for 5 hours. After removing the insoluble substance from the resultant mixture by filtration, water (300 ml.) was added to the filtrate and extracted with ethyl acetate (300 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and concentrated in vacuo. The residue was pulverized with a mixture of n-hexane, ethyl acetate and acetone (4:4:1) and then the precipitates were collected by filtration and washed with n-hexane to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-cyanomethoxyiminoacetate (syn isomer, 9.58 g.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:8]=[C:9]1[NH:28][C:12]2=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:18][C:19]=3[CH:20]=[C:11]2[NH:10]1>>[O:8]=[C:9]1[NH:28][C:12]2=[N:13][C:14]3[CH:15]=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:27])=[CH:18][C:19]=3[CH:20]=[C:11]2[NH:10]1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)CCCOc2ccc3nc4[nH]c(=O)[nH]c4cc3c2)CC1

Procedure:
Reaction of N-methylpiperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g) analogously to the procedure of Example 4 gave the title compound as the hydrated dihydrochloride salt; yield 2.85 g (92%), m.p. 286°-288° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]3[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:17]=[CH:18][C:13]3=[C:12]([N:24]3[CH2:29][C@@H:28]4[CH2:30][C@H:25]3[CH2:26][O:27]4)[N:11]=2)=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.C(OCC)(=O)C>[C@H:28]12[CH2:30][C@H:25]([N:24]([C:12]3[N:11]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=4)[N:15]=[C:14]4[N:16]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:17]=[CH:18][C:13]=34)[CH2:29]1)[CH2:26][O:27]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(N3C[C@@H]4C[C@H]3CO4)c3cnn(CC(F)(F)F)c3n2)cc1
Reaction time: 8 h

Procedure:
A suspension of (1S,4S)-5-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (0.84 mmol maximum) in tetrahydrofuran (15 mL) and ethyl acetate (15 mL) was degassed by the addition of crushed dry ice and then treated with 10% palladium on carbon (50 mg). The resulting suspension was evacuated under weak vacuum and then filled with hydrogen gas (balloon). This evacuation/fill cycle was performed three more times and on the final iteration, the mixture was left to stir overnight under a hydrogen filled balloon. The mixture was filtered through a pad of diatomaceous earth, eluting with methanol. The filtrate was concentrated under reduced pressure to afford 4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline as a white foam (0.26 g, 78% over 2 steps). MS (ES+): 391.1 (M+H)+