Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[Cl:32][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:31])[C:25]=1[NH:24][C:18]1[C:17]2[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[C:14]([O:33][CH3:34])=[CH:15][CH:16]=2)[O:21][C:20](=[O:23])[CH:19]=1
Reactant: CCCNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: CCCN(C)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from N-methylpropan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (br s, 1H), 8.58 (s, 2H), 7.86 (d, 1H), 7.06 (d, 1H), 4.24 (br s, 1H), 3.97 (t, 2H), 3.87 (s, 3H), 2.75-2.40 (br, 4H), 2.38 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.49 (m, 4H), 0.83 (t, 3H); MS (ESI): 494.0.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][C:18]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([CH2:14][OH:15])[O:12][C@@H:11]([N:41]2[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]2=[O:43])[C@@H:10]1[OH:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:51]1([CH3:61])[CH:56]=[CH:55][C:54]([S:57](Cl)(=[O:59])=[O:58])=[CH:53][CH:52]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:16][O:17][C:18]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)([CH2:14][O:15][S:57]([C:54]2[CH:55]=[CH:56][C:51]([CH3:61])=[CH:52][CH:53]=2)(=[O:59])=[O:58])[O:12][C@@H:11]([N:41]2[CH:49]=[C:47]([CH3:48])[C:45](=[O:46])[NH:44][C:42]2=[O:43])[C@@H:10]1[O:50][S:57]([C:54]1[CH:55]=[CH:56][C:51]([CH3:61])=[CH:52][CH:53]=1)(=[O:59])=[O:58])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C(OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To a solution of nucleoside 6 (2.79 g, 3.9 mmol) in anhydrous pyridine (50 cm3) was added a catalytic amount of 4-(N,N-dimethylamino)pyridine and p-toluenesulphonyl chloride (6.50 g, 34 mmol). The mixture was stirred in the dark for 24 h at room temperature under nitrogen. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate (100 cm3) and the resulting mixture was extracted with dichloromethane. The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (3×75 cm3) and sodium chloride (2×75 cm3). The separated organic phase was dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5% methanol; 0.5% pyridine, v/v) as eluent to afford nucteoside 7 (2.40 g, 62%) as a yellowish foam after evaporation of the solvents. δC ((CD3)2SO) 163.2 (C-4), 158.2, 145.9, 145.1, 144.3, 136.8, 135.0, 134.9, 134.8, 131.8, 131.6, 130.2, 130.0, 129.7, 128.2, 127.9, 127.8, 127.6, 127.5, 127.5, 127.4, 126.8, 113.3 (DMT, C-6, 2×Ts, benzyl), 150.2 (C-2), 110.8 (C-5), 95.0, 86.2 (DMT, C-4′), 82.2, 81.9 (C-1′, C-2′), 81.2 (C-3′), 72.9 (CH2Ph), 79 (C-5″), 64 (C-5′), 55.1 (2×CH3O), 21.2, 21.2 (2×CH3), 12.0 (5-CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16]OS(C)(=O)=O.[C-:22]#[N:23].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:22]#[N:23]
Reactant: COc1ccc(OC)c(C2CCCC2COS(C)(=O)=O)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(OC)c(C2CCCC2CC#N)c1
Temperature: 100 °C
Yield: 92.4 %

Procedure:
Dissolve methanesulfonic acid 2-(2,5-dimethoxy-phenyl)-cyclopentylmethyl ester (4.8 g, 15 mmol) in DMSO (25 ml), add sodium cyanide (12 g, 16 mmol), and heat at 100° C. over night. Cool to room temperature and quench with water and ethyl acetate. Separate layers, wash organic with water 3×, brine 2×, dry and concentrate to give the title compound (3.4 g 91%): 1H NMR (CDCl3) δ 6.79-6.72 (m,3H), 3.79 (s, 3H), 3.77 (s, 3H), 3.54-3.48 (m, 1H), 2.77-2.70 (m, 1H), 2.17-2.09 (m, 1H), 1.96-1.89 (m, 4H), 1.78-1.59 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14](N)=[CH:13][CH:12]=2)=[CH:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1)=[O:5])[CH3:2].Cl.N([O-])=O.[Na+].[OH-].[Na+].S(OC)([O:34][CH3:35])(=O)=O>[Cl-].[Zn+2].[Cl-].O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:34][CH3:35])=[CH:13][CH:12]=2)=[CH:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(-c2ccccc2)cc1-c1ccc(N)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: O=N[O-]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1nn(-c2ccccc2)cc1-c1ccc(OC)cc1
Reaction time: 0.5 h

Procedure:
2.4 gm. of 4-(4-aminophenyl)-1-phenyl-3-pyrazolecarboxylic acid ethyl ester are reacted with 28 ml. of 1N hydrochloric acid, cooled to 0° C. and slowly diazotized with a solution of 830 mg. of sodium nitrite in 10 ml. of water. The mixture is diluted with 10 ml. of water and stirred for 15 minutes at 0° C. Thereupon, 953 mg. of zinc chloride are added to the mixture, which is allowed to stand for 30 minutes. The separated precipitate is filtered under vacuum, dried and taken up in 50 ml. of methanol and allowed to stand at room temperature for 16 hours, and then is heated for one hour under reflux. The reaction mixture is concentrated under vacuum and the residue is dissolved in benzene. The benzene phase is washed and concentrated in vacuum. The residue is reacted with 2 equivalents of sodium hydroxide and 2.02 g. of dimethyl sulfate and heated at 80° C. for 30 minutes. After cooling, the mixture is extracted with methylene chloride, the organic phase is concentrated and the residue is recrystallized from isopropanol. 1.92 g. of 4-(4-methoxyphenyl)-1-phenyl-3-pyrazolecarboxylic acid ethyl ester with a melting point of 94° C., is obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:21][CH2:22][CH3:23])[NH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:10])[CH3:9].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1.O>CN(C)C(=O)C>[C:41]([O:40][C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:11]([C:8]([OH:7])([CH3:10])[CH3:9])[N:12]=[C:13]2[CH2:21][CH2:22][CH3:23])=[CH:27][CH:28]=1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
3.00 g of potassium t-butoxide were added, whilst ice-cooling, to a solution of 6 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 40 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 10 minutes, after which a solution of 9.00 g of t-butyl 4'-bromomethylbiphenyl -2-carboxylate in 40 ml of N,N-dimethylacetamide was added. After the reaction mixture had been stirred at room temperature for 1 hour and then at 50° C. for 2 hours, it was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 11.6 g of the title compound as a solid, softening at above 85° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:37])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30]([C:32]2[NH:33][CH:34]=[CH:35][CH:36]=2)=[O:31])=[N:7]1)=[O:5])[CH3:2].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:37])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH:29][C:30]([C:32]2[NH:33][CH:34]=[CH:35][CH:36]=2)=[O:31])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)OC(C)(C)C)sc21
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)O)sc21
Yield: 96.5 %

Procedure:
The solution of 3-{2-[(1H-Pyrrole-2-carbonyl)-amino]-benzoylamino}-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (460.8 mg, 0.88 mmol) in dioxane (10 mL) was treated with HCl 4M in dioxane (10 mL) overnight, the solvent was then removed and the residue was triturated with diethylether (Et2O, 15 mL) yielding 397 mg (96%) of the product, LC-MS: Rt 3.7; [M+H]+ 468;
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]4[OH:34])=[CH:17][CH:16]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH:22]4[O:34][CH2:36][C:37]4[CH:38]=[CH:39][C:40]5[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=5[CH:52]=4)=[CH:19][CH:20]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc4c(c3)OCO4)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccc5c(c4)OCO5)cc3)cc21

Procedure:
Analogously to Method D, 0.600 g of tert-butyl 4-{4-[3-(benzo[1,3]dioxol-5-yloxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.385 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a colourless oil. Rf=0.13 (1:2 EtOAc-heptane); Rt=5.68.
Reaction SMILES: [C:1]1([CH:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][NH:9][C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl.N1C=CC=CC=1>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:10]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:18])[NH:9]1)=[O:25]
Reactant: O=C1NNC(c2ccccc2)C1c1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1NN(C(=O)c2cccc(C(F)(F)F)c2)C(c2ccccc2)C1c1ccccc1
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A solution of 4,5-diphenyl-3-pyrazolidinone (2.0 g, 8.4 mmol) in 50 mL CH2Cl2 and 5 mL pyridine was treated dropwise with a solution of 3-trifluoromethylbenzoylchloride (1.4 g, 8.4 mmol) in 25 mL CH2Cl2 and stirred overnight. The mixture was washed with 1N HCl, dried over Na2SO4, evaporated, and the product isolated by chromatography (preparative HPLC) as 840 mg (24%) purple foam:
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(NO)(C)(C)C.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:24]([C:28]1[S:32]/[C:31](=[N:33]\[C:34](=[O:46])[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2F)/[N:30]([CH2:47][CH2:48][CH2:49][C:50]#[N:51])[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([NH:5][O:6][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:42])([F:43])[F:44])=[CH:40][C:35]=1[C:34](/[N:33]=[C:31]1\[S:32][C:28]([C:24]([CH3:25])([CH3:27])[CH3:26])=[N:29][N:30]\1[CH2:47][CH2:48][CH2:49][C:50]#[N:51])=[O:46])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(C)(C)c1nn(CCCC#N)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1CCCC#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butylhydroxylamine (133 mg, 1.50 mmol) (prepared from commercially available N-tert-butylhydroxylamine acetate (Aldrich) by adding saturated sodium bicarbonate solution and extracting the free base with ethyl ether) in anhydrous THF (10 mL) was added sodium hydride (53.9 mg, 1.35 mmol). The mixture was stirred at 0° C. for 20 min. A solution of Example 151A (310 mg, 0.75 mmol) in THF (4 mL) was added and the mixture was stirred at 22° C. for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-50% gradient) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.42 (s, 9H), 2.23-2.37 (m, 2H), 2.48 (t, J=7.1 Hz, 2H), 4.54 (t, J=6.5 Hz, 2H), 5.75 (s, 1H), 7.61 (dd, J=8.7, 2.4 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H); MS (ESI) m/z 484 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.[C:12]1(C=CCO)C=CC=CC=1.N>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][C@@H:9]2[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: OCC=Cc1ccccc1
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: N
Product: OC[C@H]1C[C@@H]1c1ccc(Br)cc1

Procedure:
The title compound was prepared by the method of A. B. Charette and H. Lebel (Organic Synthesis, 1998, 76, 86-96) substituting trans-3-(4-bromophenyl) prop-2-en-1-ol (the product of Example 1A) for 3-phenyl-prop-2-en-1-ol. 1H NMR (300 MHz, CDCl3): δ 0.92-1.0 (m, 2H), 1.45-1.48 (m, 2H), 1.76-1.85 (m, 1H), 3.61 (d, J=7.5 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 7.37 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 228 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[C:15]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:13][C:10]1[C:11]([CH3:12])=[C:2]([NH:1][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]([CH3:14])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(C)c(N)c1C
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)c(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2,4-dimethylbenzoate (1.4 g, 5.42 mmol) and cyclopentanone (2.4 mL, 27.13 mmol) in methanol (20 mL), acetic acid (0.650 g, 10.84 mmol) was added and reaction stirred at room temperature for 3 h. Then sodium cyanoborohydride (0.85 g, 13.56 mmol) was added and reaction was stirred for overnight. On completion, solvent was removed water was added and compound was extracted with ethyl acetate. Combined organic layer was collected, dried over Na2SO4 and concentrate under reduced pressure and crude material was purified by column chromatography to afford the desired compound (1.2 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]([CH2:16][CH2:17][O:18][CH3:19])[CH3:15])[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: COCCN(C)C1CCc2ccc(N)c(OC)c2CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCN(C)C1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)c2CC1
Yield: 42.5 %

Procedure:
In an analogous manner to Experimental 691, part c, 1-methoxy-N*7*-(2-methoxyethyl)-N*7*-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide were combined to yield N-[(1R,2R)-2-(5-Chloro-2-{1-methoxy-7-[(2-methoxy-ethyl)-methyl-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino)-cyclohexyl}-methanesulfonamide (185 mg, 42.5% yield) as a brown foam. 1H-NMR (CDCl3) δ 7.94 (s, 1H), 7.89 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 5.41 (m, 1H), 3.91 (m, 1H), 3.73 (s, 1H), 3.45 (m, 2H), 3.32 (m, 5H), 2.78 (m, 7H), 2.30-2.08 (m, 7H), 1.83 (br s, 2H), 1.33 (m, 7H). LC/MS (ESI+)=581 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[N:18]O)[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Cl>CO.[Pd]>[ClH:1].[NH2:18][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)=[O:10]
Reactant: O=C(C(=NO)c1ccnc(Cl)c1)c1ccc(F)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
With gentle heating, 22a (1.5 g; 5.4 mmol) was dissolved in methanol (15 ml). The solution was cooled to room temperature, HCl-containing methanol (20 ml) was added and the mixture was transferred into a two-necked flask. Pd—C 10% (150 mg) was introduced into the initial charge. The reaction vessel was evacuated using an oil pump, and H2 was then introduced via a gas inlet capillary (4×). At room temperature, the suspension was shaken in a closed three-necked flask under an atmosphere of H2 (240 strokes/min) until no more starting material could be detected by thin-layer chromatography (6 h). The suspension was filtered and the catalyst was washed with plenty of methanol. The combined filtrate was concentrated and the mustard-colored solid-amorphous residue was dried using an oil pump. The crude product was used without further purification for the next reaction step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:23]3[S:22][CH:26]=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)[CH3:13])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)N[C@H](C)c2ccc(Br)cc2)s1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: COC(=O)c1ccc(C(=O)N[C@H](C)c2ccc(-c3cccs3)cc2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
To a suspension of 0.462 g (0.0004 mol) tetrakis(triphenylphosphine)-palladium(0) in 45 ml dry dimethoxyethane, 5.00 g (0.0136 mol) (R)-5-[1-(4-bromo-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester were added and stirred for 10 min at room temperature under nitrogen atmosphere. 3.65 g (0.0285 mol) thiophene-2-boronic acid in 20 ml ethanol and 14.3 ml (0.0286 mol) of a 2 M aqueous solution of Cs2CO3 were added and the mixture was heated to 75-80° C. for 3 hours. After 1.25 hours, another 0.5 equivalents of thiophene-2-boronic acid and Cs2CO3 were added to the mixture. The warm reaction mixture was filtered, the solid was washed with ethyl acetate and the solvent of the filtrates was evaporated. The residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate and the solvent was removed. The crude product was recrystallized from n-butanol/n-heptane 1:2 and dried in vacuum to give 2.52 g (0.00678 mol) (R)-5-[1-(4-thiophen-2-yl-phenyl)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C@@H:15]([C:19]([OH:21])=[O:20])[C@H:16]([CH3:18])[OH:17].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:14][C@H:15]([C@@H:16]([OH:17])[CH3:18])[C:19]([OH:21])=[O:20])=[CH:3][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:7]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Temperature: 75 °C
Reaction time: 24 h
Yield: 55.6 %

Procedure:
4-fluoro-2-(trifluoromethyl)benzonitrile (194853-86-6) (2.0 g, 10.6 mmol) was mixed together with H-D-Thr-OH (1.51 g, 12.69 mmol) in DMSO (30 mL). K2CO3 (3.06 g, 22.21 mmol) was added to the reaction mixture and stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the pure final product (1.7 g): 1H NMR (500 MHz, CDCl3, δ in ppm) 9.02 (br s, 1H), 7.76 (d, J=9 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J=9 Hz, 1H), 6.41 d, J=9 Hz, 1H), 4.42 (m, 1H), 4.01 (m, 1H), 1.24 (d, J=6 Hz, 3H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=O)(=O)C.[C:11]([CH:16]1[CH2:24][CH:23]2[CH:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[NH:17]1)([O:13]CC)=[O:12].C(C1CC2C(=CC=CC=2)N1)(OCC)=O>>[SH:4][CH2:5][CH:6]([CH3:10])[C:7]([N:17]1[CH:18]2[CH:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:24][CH:16]1[C:11]([OH:13])=[O:12])=[O:9]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: CCOC(=O)C1CC2CCCCC2N1
Agent: CCOC(=O)C1Cc2ccccc2N1
Product: CC(CS)C(=O)N1C(C(=O)O)CC2CCCCC21

Procedure:
Using the method described in example 1, beginning with 3-acetylthio 2-(RS) methylpropionic acid and 2-(RS) carbethoxy perhydroindole, prepared by reduction of 2(RS) carbethoxy indoline according to the method described in example 13, the following are obtained successively:
Reaction SMILES: CC([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[C:31]([F:32])=[CH:30][C:29]([N+:33]([O-])=O)=[C:28]([NH2:36])[C:27]=2[F:37])=[CH:21][CH:20]=1)C(=O)[O-])(C)C>C(OCC)(=O)C.[Pd]>[NH2:36][C:28]1[C:27]([F:37])=[C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][NH:14][CH:6]3[CH2:5][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[CH:24][CH:23]=2)[C:31]([F:32])=[CH:30][C:29]=1[NH2:33]
Reactant: CC(C)(C)C1c2ccccc2CC1N(Cc1ccc(Oc2c(F)cc([N+](=O)[O-])c(N)c2F)cc1)C(=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(F)c(Oc2ccc(CNC3Cc4ccccc4C3)cc2)c(F)c1N

Procedure:
1,1-dimethylethyl({4-[(3-amino-2,6-difluoro-4-nitrophenyl)oxy]phenyl}methyl)2,3-dihydro-1H-inden-2-ylcarbamate (114 mg) was dissolved in ethyl acetate and hydrogenated over 10% Pd on carbon (wet, degussa type) with Parr hydrogenator at 45 psi. The catalyst was removed by filtration through celite. The filtrate was concentrated to give [2-amino-4-({4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]phenyl}oxy)-3,5-difluorophenyl]amine which was used without further purification.