Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CO[C:6]([S:8][CH:9]2[N:12]([C:13](=C(N3CCOCC3)CBr)[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:36])[CH:10]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:52][OH:53].Cl>C(Cl)Cl>[OH:53][C:52]1[CH2:6][S:8][C@@H:9]2[CH:10]([NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:11](=[O:36])[N:12]2[C:13]=1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: CO
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(CBr)N2CCOCC2)C1SC(=O)OCC1CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 63 %

Procedure:
To a solution of p-nitrobenzyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(morpholin-4-yl)ethylidene]acetate (151 mg) in methylene chloride (1.5 ml) is added aluminum chloride (0.42 mg) and the mixture is stirred for 50 minutes under ice cooling. The mixture is diluted with ice water (2 ml), stirred for 5 minutes, and stirred with a mixture (15 ml) of methanol and methylene chloride (5:1) after addition of 10% hydrochloric acid (3 ml) at room temperature for 80 minutes. The reaction mixture is diluted with ice water, and is extracted with chloroform. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (63 mg). Yield: 63%. This product is identical with the product of Example 4.-III(3) produced by hydrolysis of the 4-morpholino group to be replaced with the corresponding hydroxy group.
Reaction SMILES: C([O:8][C:9](=[O:33])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:32])[C@@H:16]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:17][S:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH2:21]([S:18]([NH:17][C@@H:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:33])=[O:8])=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:20])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [H][H]
Reactant: CC(C)C[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 101 %

Procedure:
N-benzylsulfonyl-D-leucyl-L-proline benzyl ester (1.2 g) was dissolved in methanol (20 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (981 mg, 97%), which was directly used for the next reaction.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([O:17]C)=[O:16])=[CH:10][CH:11]=2)[N:6]=1.[OH-].[Li+]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:15]([OH:17])=[O:16])=[CH:10][CH:11]=2)[N:6]=1
Reactant: COC(=O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Reaction time: 60 h
Yield: 39.8 %

Procedure:
To a solution of methyl 2-((2,2,2-trifluoroethyl)amino)quinoline-7-carboxylate (172 mg, 0.605 mmol) in tetrahydrofuran (5 mL) was added aqueous lithium hydroxide (1.82 mL, 1.82 mmol, 1M solution) at room temperature. The reaction was stirred for 2.5 days. The solvent was removed under reduced pressure and the residue was acidified with 1N aqueous hydrochloric acid. The resulting precipitate was filtered and dried to give the title compound (65 mg, 40%) +ESI (M+H) 271.1, 1H NMR (400 MHz, DMSO-d6, δ): 4.31-4.41 (m, 2H) 7.01 (d, J=8.87 Hz, 1H) 7.69-7.80 (m, 2H) 8.06 (d, J=8.66 Hz, 1H) 8.14 (s, 1H) 13.03 (bs, 1H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[C:11]([N+:16]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[N:3]1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[C:10]=3[CH:9]=[CH:8]2)=[N:3]1
Reactant: Cn1ccc(-n2ccc3c([N+](=O)[O-])cccc32)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1ccc(-n2ccc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10% Palladium-carbon (500 mg) was added to a solution of 1-(1-methyl-1H-pyrazol-3-yl)-4-nitro-1H-indole obtained in the above-described Step 1 (625 mg) in ethyl acetate (20 ml) under nitrogen airflow. Then the reaction solution was stirred under hydrogen atmosphere at room temperature for 2 hours and a half. The insolubles were filtrated with celite, and then the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 1-(1-methyl-1H-pyrazol-3-yl)-1H-indol-4-amine.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]=2[CH:8]=1.C1COCC1>CO>[CH3:3][C:4]1[O:5][C:6]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[C:9]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:7]=2[CH:8]=1
Reactant: COC(=O)c1cc(OCC(C)C)c2cc(C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2c(OCC(C)C)cc(C(=O)O)cc2o1
Temperature: 50 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Sodium hydroxide solution (2.28 ml of 1M, 2.28 mmol, 3 eq) was added to a solution of 2-methyl-4-isobutoxy-6-methoxycarbonylbenzofuran (Method 7; 200 mg, 0.76 mmol; contained ca 15 mol % of isobutyl ester) in MeOH (2.28 ml)/THF (2.28 ml). After 2 hours at 50° C. the reaction mixture was stirred at ambient temperature overnight and then concentrated to half-volume in vacuo. The resulting solution was diluted with water and acidified to pH 5 (1M HCl), and the resulting flocculent precipitate filtered and dried to give the title compound as a colourless solid (165 mg, 88%). NMR: 1.02 (d, 6H), 2.06 (sept, 1H), 2.45 (s, 3H), 3.90 (d, 2H), 6.64 (s, 1H), 7.24 (s, 1H), 7.64 (s, 1H), 12.83 (bs, 1H); m/z 247 (M−H)−, 94.6% by LC-MS.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Reactant: NCc1ccc(F)cc1
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccc(F)cc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH2:29].CCCCCC>CCOC(C)=O>[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH:29][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:14]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Yield: 94.6 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-nitro-phenyl)-propionic acid (1.95 g, 10.0 mmol), SOCl2 (3.6 mL, 33.4 mmol), and 2-amino-4-chloro-benzoic acid methyl ester (1.24 g, 6.67 mmol). After normal workup, the pure objective compound (2.29 g, 95%) was obtained as slightly yellow solid by a flash column chromatography (n-hexane:EtOAc=8:1): 1H NMR (200 MHz, CDCl3) δ 1.65 (d, J=7.3 Hz, 3H, CH3), 3.83-3.93 (m, 4H, CO2CH3 & CH), 7.04 (dd, J=8.5, 2.0 Hz, 1H, ArH), 7.58 (d, J=8.9 Hz, 2H, ArH), 7.93 (d, J=8.5 Hz, 1H, ArH), 8.21 (d, J=8.9 Hz, 2H, ArH), 8.79 (d, J=2.0 Hz, 1H, ArH), 11.09 (br s, 1H, NH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:45][C:41]3[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccnc4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and Pyridin-3-ylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-pyridin-3-yl-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (23 mg, 47%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.99 Hz, 6 H) 3.29 (m, 1 H) 6.78 (m, 2 H) 6.95 (m, 3 H) 7.54 (dd, J=8.27, 4.96 Hz, 1 H) 7.90 (d, J=8.82 Hz, 1 H) 8.02 (dd, J=8.82, 2.21 Hz, 1 H) 8.16 (d, J=2.21 Hz, 1 H) 8.29 (m, 1 H) 8.39 (dd, J=4.78, 1.47 Hz, 1 H) 8.94 (s, 1 H) 9.04 (m, 2 H) 9.48 (s, 1 H) 10.59 (s, 1 H) 11.59 (s, 1 H); MS (ESI+) m/z 493 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH:24]C(=O)OC(C)(C)C)=[N:14][CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:17]=3)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[O:11][C:10]([C:12]3[C:13]([NH2:24])=[N:14][CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:17]=3)=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Tert-butyl 3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-(piperazin-1-yl)pyrazin-2-ylcarbamate (2.29 g, 5.408 mmol) was dissolved in DCM (20 mL) and treated with TFA (5 mL, 64.90 mmol) was added. The reaction was allowed to stir for 1 hour at ambient temperature and then the solvent removed in vacuo. The mixture was treated with NaHCO3/brine and EtOAc and the 2 layers separated layers. The aqueous layer was extracted with EtOAc, followed by DCM and CHCl3. The mixture was dried over MgSO4, filtered and concentrated to give the product as an orange solid (1.44 g, 82% Yield). 1H NMR (400.0 MHz, DMSO) d 3.00 (4H, br m), 3.43 (4H, br m), 6.05 (2H, br s), 7.20 (1H, m), 7.34 (2H, m), 7.90 (1H, m), 8.13 (2H, m) ppm; (ES+) 324.03
Reaction SMILES: Cl.C([O:5][C@H:6]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[S:8][C@H:7]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=O)C.[OH-].[K+]>C(O)C>[CH3:18][N:16]([CH3:17])[CH2:15][CH2:14][N:11]1[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[S:8][C@@H:7]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C@@H:6]([OH:5])[C:12]1=[O:13]
Reactant: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reaction time: 1.5 h

Procedure:
30 Grams (0.0665 mole) of cis-(+)-3-acetoxy-2,3-dihydro-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one hydrochloride were added to a solution of 7.5 g (0.1337 mole) of potassium hydroxide in 450 ml of ethanol. The resulting mixture was kept at room temperature for 90 minutes, then the solvent was evaporated off in vacuo, the residue was taken up with water and subsequently extracted with CHCl3. The organic phase wase washed with water, in order to remove the excess of alkali, then dried over sodium sulfate. After evaporating the solvent under vacuum, 24.26 g of a glassy paste which became solid upon standing overnight at room temperature was obtained. It was finally ground and used as such for the subsequent reactions.
Reaction SMILES: COC(OC)CN.C(OC(=O)C)(=O)C.COC(OC)[CH2:18][NH:19][C:20](=[O:22])[CH3:21].[F:25][C:26]1[CH:27]=[C:28]([S:32]([C:35]2[CH:36]=[CH:37][C:38]3[O:42][CH:41]=[C:40]([CH2:43][CH2:44][NH:45][C:46](=O)OC(C)(C)C)[C:39]=3[CH:53]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>ClCCCl.ClCCCl.C(O)(C(F)(F)F)=O>[F:25][C:26]1[CH:27]=[C:28]([S:32]([C:35]2[CH:36]=[CH:37][C:38]3[O:42][C:41]4[CH:46]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[NH:45][CH2:44][CH2:43][C:40]=4[C:39]=3[CH:53]=2)(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: COC(CNC(C)=O)OC
Reactant: CC(C)(C)OC(=O)NCCc1coc2ccc(S(=O)(=O)c3cccc(F)c3)cc12
Agent: COC(CN)OC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCC1NCCc2c1oc1ccc(S(=O)(=O)c3cccc(F)c3)cc21
Reaction time: 0.17 h

Procedure:
2,2-Dimethoxyethylamine (16 μL, 1.5 eq) was dissolved in DCE (400 μL), acetic anhydride (15 μL, 1.5 eq) was added and the solution was shaken for 10 min. The resulting solution of N-(2,2-dimethoxyethyl)acetamide in DCE was added to a solution of tert-butyl (2-{5-[(3-fluorophenyl)sulfonyl]-1-benzofuran-3-yl}ethyl)carbamate (800 μL, 0.125 M) in DCE:TFA 1:1. The reaction mixture was shaken at 100° C. for 16 h and the solvent was evaporated. The crude product was purified by preparative LC/MS and concentrated to afford the product as a trifluoroacetic acid salt. MS m/z 403 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[C:62]([O:66][C:67]([N:69]1[CH2:73][CH2:72][C@@H:71]([C:74]2[CH:79]=[CH:78][C:77]([SH:80])=[CH:76][CH:75]=2)[CH2:70]1)=[O:68])([CH3:65])([CH3:64])[CH3:63].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.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]>[C:62]([O:66][C:67]([N:69]1[CH2:73][CH2:72][C@@H:71]([C:74]2[CH:79]=[CH:78][C:77]([S:80][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][N:6]=[CH:5]4)=[CH:76][CH:75]=2)[CH2:70]1)=[O:68])([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S)cc2)C1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(Sc3ccc4[nH]ncc4c3)cc2)C1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
5-Bromo-1H-indazole (200.9 mg, 1.02 mmol), Pd2(dba)3 (115.9 mg), Xantphos (145.9 mg) and DIPEA (0.188 mL) were added to a solution of (S)-3-(4-mercapto-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (285 mg, 1.02 mmol) in 1,4-dioxane (4 mL) under argon atmosphere. The reaction mixture was heated at 100° C. for 18 hours, then cooled to 5° C. and a solution of 10% KHSO4/Na2SO4 was added. The mixture was filtered, the filter cake was washed with EtOAc, and the filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 7/3) to give 252 mg (62% yield) of (S)-3-[4-(1H-indazol-5-ylsulfanyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([CH2:30][NH:31][C:32]2[S:36][N:35]=[C:34]([C:37]3[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=3)[CH:33]=2)[CH2:29][CH2:28]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([C:34]2[CH:33]=[C:32]([NH:31][CH2:30][CH:27]3[CH2:29][CH2:28]3)[S:36][N:35]=2)=[CH:44][CH:43]=1
Reactant: NCc1ccc(-c2cc(NCC3CC3)sn2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(-c4cc(NCC5CC5)sn4)cc3)c2CC1)C(F)(F)F
Yield: 39.5 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (75 mg, 0.18 mmol) with 4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamine (68 mg, 0.26 mmol) in toluene (3 mL). Purify the crude mixture by chromatography on silica gel (4 g) eluting with hexane/EtOAc with 2% methanol (9:1 to 4:1 gradient) to obtain 7-chloro-6-{4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (38 mg, 40%). MS (ES+) m/z: 535.3 (M+H)4.
Reaction SMILES: CO[CH:3]([C:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])[S:10][C:6]=2[CH:5]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>CC#N>[NH:23]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:29]2[C:21]([CH2:3][C:4]2[CH:20]=[CH:19][C:7]3[N:8]=[C:9]([NH:11][C@@H:12]4[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]4[OH:18])[S:10][C:6]=3[CH:5]=2)=[CH:22]1
Reactant: COC(c1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3c[nH]c4ncccc34)cc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To a solution of (1R,2R)-2-((6-(methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 0.049 mmol) from Step 3 of Example 12 in CH3CN (10 mL) were added triethylsilane (11.4 mg, 0.092 mmol) and TFA (10.4 mg, 0.092 mmol) at rt. The mixture was stirred at 60° C. overnight. After cooling to rt, the reaction mixture was concentrated under reduced pressure. The crude product was purified by HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (5.7 mg, 31%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 11.71 (br s, 1H), 9.56 (br s, 1H), 8.23 (d, J=4.1 Hz, 1H), 7.93 (d, J=7.0 Hz, 1H), 7.70 (s, 1H), 7.26-7.42 (m, 3H), 7.07 (dd, J=4.9, 7.9 Hz, 1H), 4.11 (s, 2H), 3.53 (br s, 1H), 3.27-3.43 (m, 2H), 1.83-2.12 (m, 2H), 1.66 (br s, 2H), 1.27 (br s, 4H). LCMS (ESI) m/z 379 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][OH:10])=[CH:7][C:6]([CH2:11][CH3:12])=[C:5]([CH3:13])[N:4]=1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:13])[C:6]([CH2:11][CH3:12])=[CH:7][C:8]=1[CH:9]=[O:10]
Reactant: CCc1cc(CO)c(OC)nc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: CCc1cc(C=O)c(OC)nc1C
Yield: 90.1 %

Procedure:
Activated manganese dioxide (2.0 g) was added to a solution of 2-methoxy-3-hydroxymethyl-5-ethyl-6-methylpyridine (1.18 g, 6.5 mmol) in dry benzene (20 mL) and refluxed 5-10 hours. The warm suspension was filtered through a pad of anhydrous Na2SO4 and evaporated to yield 1.05 g (90%) of a viscous oil which solidified.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH2:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C>ClCCl>[C:5]([N:9]([CH3:36])[C:10]([C:12]1[N:16]2[CH2:17][CH2:18][C:19]3[C:24]([C:15]2=[C:14]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[N:13]=1)=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:1](=[O:3])[CH3:2])=[C:21]([O:29][CH3:30])[CH:20]=3)=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: COc1cc2c(cc1OCCN)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OCCNC(C)=O)-c1c(-c3cccs3)nc(C(=O)N(C)C(C)(C)C)n1CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetyl chloride (10.2 μl) was added dropwise to a mixture of the product of example 31 (50 mg) and DIPEA (55 μl) in dichloromethane (2 ml). After stirring at room temperature for 18 h, the reaction mixture was diluted with dichloromethane and washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (0→100% acetonitrile).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:11])[CH2:9][CH3:10].Cl.[NH2:14][CH:15]1[C:27](=[O:28])[C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1>C(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16][CH:15]1[NH:14][C:8](=[O:11])[CH2:9][CH3:10]
Reactant: NC1CCc2cc3c(cc2C1=O)OCC3
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC1CCc2cc3c(cc2C1=O)OCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23 ml of triethylamine and 5.7 ml of propionyl chloride are added in succession to 17 g of dl-7-amino- 2,3,6,7-tetrahydro-5H-naphtho[2,3-b]furan-8-one hydrochloride suspended in 170 ml of methylene chloride. After 2 hours' stirring at room temperature, the reaction mixture is washed with water, decanted and concentrated to dryness. 20 g of the desired compound are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:27][CH:26]=[N:25][CH:24]=1)CCC.CCOC(C)=O.[F-].[K+]>C1(C)C=CC=CC=1.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>[N+:15]([C:12]1[N:11]=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:23]3[S:27][CH:26]=[N:25][CH:24]=3)[CH:7]=2)=[CH:14][CH:13]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Temperature: 110 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
A solution of Example A1 (0.3 g, 1.192 mmol) in toluene (10 mL) was sparged with Ar, treated with 5-(tributylstannyl)thiazole (0.446 g, 1.192 mmol), Pd(PPh3)4 (0.138 g, 0.119 mmol) and heated at 110° C. for 16 h. The mixture was cooled to RT, treated with EtOAc and 10% aq. KF solution (30 mL) and stirred for 1 h. The solids were removed via filtration through diatomaceous earth, and the layers of the filtrate were separated. The aqueous layer was extracted with additional EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (180 mg, 50%) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 8.64-8.63 (m, 2H), 8.57 (d, J=5.7 Hz, 1H), 8.43 (d, J=8.9 Hz, 1H), 8.04 (dd, J=8.9, 2.8 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.15 (dd, J=5.7, 2.4 Hz, 1H); MS (ESI) m/z: 301.1 (M+H+).