Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[CH3:13][C:14]1([CH3:27])[C:18]2([CH2:22][S:23](Cl)(=[O:25])=[O:24])[C:19]([CH2:21][CH:15]1[CH2:16][CH2:17]2)=[O:20]>C(Cl)Cl.C(N(CC)CC)C>[CH:4]1([CH2:3][CH2:2][NH:1][S:23]([CH2:22][C:18]23[C:14]([CH3:13])([CH3:27])[CH:15]([CH2:16][CH2:17]2)[CH2:21][C:19]3=[O:20])(=[O:25])=[O:24])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: NCCC1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CCC1(CS(=O)(=O)NCCC1CCc3ccccc31)C(=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indene (2 ml), 1.99 g, 17.2 mmol) was dissolved in dry THF (2 ml) and stirred at -78° under nitrogen. n-Butyllithium (6.87 ml of a 2.5M solution in hexane: 17.2 mmol) was added, and the solution was then warmed to ambient temperature, stirred for 15 minutes, recooled to -78°, and added via syringe to a solution of chloroacetonitrile (1.09 ml, 1.30 g, 17.2 mmol) in THF (2 ml) stirred at -78°. After completion of the addition, the solution was diluted with ether (200 ml) and washed with 1M HCl followed by saturated sodium bicarbonate solution. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 10% EtOAc in hexane and the product fractions evaporated in vacuo to give 3-cyanomethylindene. 3-Cyanomethylindene (310 mg, 2.0 mmol) was dissolved in a 10% solution of conc. ammonium hydroxide in absolute ethanol. 5% Rhodium/alumina catalyst (60 mg) was added and the mixture was shaken under an atmosphere of hydrogen (40 psi) overnight. The mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 93:7:0.7 CH2Cl2 :MeOH:NH4OH, and the product fractions were combined and evaporated to dryness in vacuo to provide 1-(2-aminoethyl)indane. 1-(2-Aminoethyl)indane (47 mg, 0.292 mmol) and (+)-10-camphorsulfonyl chloride (73 mg, 0.29 mmol) were combined in CH2Cl2 (2 ml), treated with triethylamine (2 drops), and stirred at ambient temperature overnight. The mixture was evaporated to dryness in vacuo and the residue chromatographed on a silica gel column eluted in with 20% EtOAc in hexane. The product fractions were combined and evaporated to dryness in vacuo. The resulting oil was dried in vacuo at ambient temperature for 3 hours to provide the title compound as a solid: (mp 52°-70°).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.CS(O[CH:12]1[CH2:27][CH2:26][C:15]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:14][CH2:13]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH:12]2[CH2:27][CH2:26][C:15]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16]3)[CH2:14][CH2:13]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CCC(OS(C)(=O)=O)CC2)C1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(CCC(n3cc(I)cn3)CC2)C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 4-iodo-1H-pyrazole and tert-butyl 7-(methylsulfonyloxy)-2-azaspiro[3.5]nonane-2-carboxylate (70 mg, 0.219 mmol, 1.0 equiv) and 4-iodo-1H-pyrazole in DMF (1 mL) was added Cs2CO3 (79 mg, 0.241 mmol, 1.1 equiv). The mixture was stirred at 80° C. for 3 hrs. It was concentrated by rotary evaporator in vacuo to give the residue which was purified by CombiFlash (12 g silica gel column, EtOAc/Hex: 0-40%) to afford 74 mg (yield 81%) of tert-butyl 7-(4-iodo-1H-pyrazol-1-yl)-2-azaspiro[3.5]nonane-2-carboxylate as a off-white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]>>[Cl:37][C:38]1[CH:43]=[C:42]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:24]3)=[N:21][CH:22]=2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54]
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 78.4 %

Procedure:
Following general procedure II, (S)-tert-butyl (1-(5-((6-chloro-3-propionyl-1,5-naphthyridin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)carbamate (100 mg, 0.20 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.30 mmol) to afford the product (100 mg) which was carried forward without any purification: ESI MS m/z 637 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([OH:23])=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:39][C@H:40]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:41]([CH3:43])[CH3:42].S(C1C=CC(C)=CC=1)([O-])(=O)=O>CN(C=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:21]([NH:39][C@H:40]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:23])[CH2:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -15 °C
Yield: 103.3 %

Procedure:
A solution, cooled to -20° C., of 32.3 g of Boc-Asp-(OBzl)-OH in 150 ml of DMF is treated with 11 ml of N-methylmorpholine and 13.07 ml of isobutyl chloroformate. The suspension obtained is stirred at -15° C. and treated with a suspension, cooled to -20° C., of 37.95 g of H-Val-OBzl.tosylate and 11 ml of N-methylmorpholine in 150 ml of DMF. The reaction mixture is stirred at below -10° C. for 10 minutes and at room temperature for 2 hours, filtered and the filtrate is concentrated. The residue is dissolved in ethyl acetate and washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution and dried. The organic phase is concentrated. 52.9 g of Boc-Asp(OBzl)-Val-OBzl are obtained. 10.24 g thereof are dissolved in 30 ml of TFA and then concentrated. The residue, is crystallized from ethyl acetate/hexane. There are obtained 8.3 g of H-Asp- (OBzl)-Val-OBzl.TFA (1:1),.m.p. 147°-148° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[NH2:23][C:24]1[N:25]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:26]=[C:27]2[C:32]=1[CH:31]=[CH:30][C:29]([C:33]1[CH:34]=[C:35]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[N:36]3[C:41]=1[C:40]([NH2:42])=[N:39][CH:38]=[N:37]3)=[CH:28]2.CCOC(C)=O>C1COCC1.ClCCCl>[C:2]([O:5][C:6](=[O:7])[N:8]([CH2:10][C:11]([N:46]1[CH2:47][CH2:48][CH:43]([C:35]2[N:36]3[C:41]([C:40]([NH2:42])=[N:39][CH:38]=[N:37]3)=[C:33]([C:29]3[CH:30]=[CH:31][C:32]4[C:27]([CH:28]=3)=[N:26][N:25]([CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:24]=4[NH2:23])[CH:34]=2)[CH2:44][CH2:45]1)=[O:13])[CH3:9])([CH3:1])([CH3:3])[CH3:4]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c12
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC(=O)N1CCC(c2cc(-c3ccc4c(N)n(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 37.1 %

Procedure:
To a stirred solution of N-t-BOC-sarcosine (44.0 mg, 0.233 mmol, 1.2 eq), ByPOP (120 mg, 0.27 mmol, 1.4 eq), and diisopropylethylamine (0.10 mL, 0.58 mmol, 3.0 eq) in anhydrous THF (1.9 mL) and DCE (1.0 mL) was added 5-(3-amino-2-benzyl-2H-indazol-6-yl)-7-piperidin-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (85 mg, 0.194 mmol). The reaction mixture was stirred at 40° C. under N2 for 18 h and cooled to rt. The mixture was cooled and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in anhydrous THF (2.0 mL), and 1.0 M sodium methoxide in MeOH (0.5 mL) was added. The reaction mixture was stirred at it for 18 h and poured into EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO® instrument (gradient 0 to 25% MeOH/EtOAc) and the product containing fractions were concentrated. Trituration with DCM-hexane afforded 43.9 mg (37.2%) of the title compound as pink solid. 1H NMR (300 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.71 (d, 1H), 7.34 to 7.29 (m, 2H), 7.27 to 7.14 (m, 3H), 7.15 (t, 1H), 6.73 (t, 1H), 6.56 (s, 0.5H), 6.48 (s, 0.5H), 6.37 (s, 2H), 5.38 (s, 2H), 4.50 to 4.45 (m, 1H), 4.13 to 3.83 (m, 3H), 3.44 to 3.35 (m, 1H), 3.16 (t, 1H), 2.78 to 2.70 (m, 4H), 2.07 to 2.04 (m, 2H), 1.66 to 1.51 (m, 2H), 1.35 (d, 9H); ES-MS m/z 610.0 [M+H]+, RT (min) 2.55.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1>CN(C=O)C>[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[N:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=4)[C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.011 g, 0.27 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, from Example 2, Step 5) in DMF (6 mL). After stirring for 10 minutes, 1-(chloromethyl)-3-nitro-benzene, (0.058 g, 0.34 mmol, Aldrich) was added. After stirring for 45 minutes, the reaction was quenched by the addition of water and the mixture was diluted with MeCN, filtered and purified via preparative HPLC-MS to afford product as a yellow solid (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (0.065 g, 75%).
Reaction SMILES: C[Al](C)C.[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=CC=1.[OH:12][CH:13]([CH2:18][CH3:19])[CH2:14][C:15]([O-:17])=[O:16].Cl>ClCCl>[S:11]1[CH:8]=[CH:9][CH:10]=[C:5]1[O:17][C:15](=[O:16])[CH2:14][CH:13]([OH:12])[CH2:18][CH3:19]
Reactant: Sc1ccccc1
Reactant: CCC(O)CC(=O)[O-]
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CCC(O)CC(=O)Oc1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a dry flask on ice, 3 ml of dehydrated dichloromethane was stirred and 1 ml of 2M trimethyl aluminum was slowly added thereto under a nitrogen stream. After that, 1 mmol of thiophenol was slowly added thereto. The mixture was stirred at room temperature for 30 minutes and then 3-hydroxyvalerate dissolved in 3 ml of dehydrated dichloromethane was added thereto. The reaction was monitored by a TLC. To this mixed solution was added 10 ml of dichloromethane and, until generation of bubbles stopped, 10 ml of 3% hydrochloric acid solution was added. The mixed solution was transferred to a separating funnel, washed with 3% hydrochloric acid solution for two times and with saturated saline for two times, dried over magnesium sulfate and evaporated in vacuo to give 258 mg of crude oily 3-hydroxyvalerate thiophenyl ester in dark yellow color. This was purified by a column chromatography (20 cm×1 cm diameter; eluent was hexane:ethyl acetate=2:1) using silica gel 60 to give 44 mg of pure 3-hydroxyvalerate thiophenyl ester as a transparent oil. The yield to the unpurified substance was 17%. Result of NMR analysis of this compound is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[CH:26]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]([CH:26]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:22]([O:24][CH3:25])=[O:23])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: BrC1CCCCCCC1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(OC)c1)C1CCCCCCC1

Procedure:
7.68 g (23 mmol) of the compound from Example XXIII and 4.4 g (23 mmol) of cyclooctyl bromide are dissolved in 100 ml of dimethylformamide. 3.36 g (30 mmol) of potassium tertiary butoxide, dissolved in 30 ml of DMF, are added dropwise to this mixture at 0°-10° C. with stirring. The mixture is subsequently stirred at room temperature for a further two hours and then treated with 30 ml of 1N hydrochloric acid. The solvent is then evaporated in vacuo, the residue is taken up in 200 ml of dichloromethane and the dichloromethane solution is washed twice with 100 ml of water. After drying with sodium sulphate, it is concentrated to a small volume in vacuo and the residue is separated by column chromatography (silica gel 60, eluent: toluene/ethyl acetate=4:1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[Cl:15][C:16]1[CH:25]=[C:24]([NH:26][C:12]([C:6]2[O:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1Cl
Yield: 71.4 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylfuran-2-carboxylic acid (80 mg, 0.408 mmol) and methyl 2-chloro-4-aminobenzoate (136 mg, 0.733 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-chloro-4-[(4,5-diisopropylfuran-2-carbonyl)amino]benzoate (106 mg, 72%) as colorless prisms.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([OH:20])=O)=[N:9]2)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=3)[C:10]([C:18]([Cl:23])=[O:20])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nccc(-n2nc(C(=O)Cl)c3ccc(I)cc32)n1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (1.00 g, 2.62 mmol) in DCM (10 mL), was added thionyl chloride (1.9 ml, 26.24 mmol)) followed by a drop of DMF. The mixture was stirred at 50° C. for 45 minutes. The reaction mixture was concentrated in vacuo and DCM (5 mL) was added and the concentration repeated (×2). The crude acid chloride was used directly in the next step: LC-MS m/z=+395.95 (M+H)+(after conversion to methyl ester derivative)
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[NH2:14][C:12]1[C:11]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1
Reactant: CC(C)(C)c1nc2cc(N3CCOCC3)c([N+](=O)[O-])cc2s1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1nc2cc(N3CCOCC3)c(N)cc2s1

Procedure:
A solution of 173 g of 2-tert-butyl-5-[morpholin-4-yl]-6-nitrobenzothiazole in 5000 ml of methanol is hydrogenated in presence of 40 g of Raney Nickel at room temperature. After removing the catalyst the solution is concentrated and the solid filtered to give 6-amino-2-tert-butyl-5-morpholinobenzothiazole, melting at 158°-159°.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:36]=[CH:35][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18]C(C)(C)C)=[O:17])=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([OH:18])=[O:17])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(CO)cc2)cc1Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccc(CO)cc2)cc1Nc1ccc(F)cc1
Yield: 3.6 %

Procedure:
Trifluoroacetic acid 5.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-(4-(hydroxymethyl)phenyl)benzoate 64 mg was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure,diisopropyl ether and hexane were added to the obtained residue, solid matter was filtrated to give 2-(4-fluoroanilino)-4-(4-(hydroxymethyl)phenyl)benzoic acid 2.0 mg of a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:30][C:31]([NH2:33])=[NH:32]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:2]3[C:3]=2[C:4]([NH2:5])=[N:32][C:31]([NH2:33])=[N:30]3)[CH2:17][CH2:16]1
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCC(Cc2ccccc2F)CC1
Agent: O=C(O)O
Product: Nc1nc(N)c2c(OCC3CCC(Cc4ccccc4F)CC3)cccc2n1
Yield: 52 %

Procedure:
Cyclization of 2-fluoro-6-[4-(2-fluorobenzyl)cyclohexylmethoxy]benzonitrile (225 mg; 0.66 mmol) and guanidine carbonate (119 mg; 0.66 mmol) was carried out using Method F. Material was purified using ethyl alcohol trituration. Solids were collected by filtration. Title compound was obtained. (130 mg; 52% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.33 (t, J=8.0 Hz, 1H), 7.24 (m, 4H), 7.12 (m, 2H), 6.75 (dd, J=8.4, 0.8 Hz, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.97 (br s, 2H), 3.92 (d, J=5.6 Hz, 2H), 2.52 (d, J=7.2 Hz, 2H), 1.83 (m, 3H), 1.69 (m, 2H), 1.51 (m, 1H), 1.06 (m, 4H). MS m/z (APCI) 381 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:12]([C:13]3[C:14]([NH:19][CH2:20][CH3:21])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][S:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)C>O1CCCC1.C(OCC)(=O)C>[CH3:21][CH2:20][N:19]1[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:8](=[CH:9][S:10][CH:11]=2)[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=2
Reactant: CCNc1ncccc1-c1cscc1-c1cccnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN1c2ncccc2-c2cscc2-c2cccnc21
Reaction time: 0.08 h

Procedure:
To a solution of 3-(2-fluoropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.021 g) in tetrahydrofuran (1.5 mL was added potassium bistrimethylsilylamide (0.5M in toluene) until no yellow color appeared on addition of further reagent. The mixture was stirred for 5 minutes, ethanol was added, the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. The residue was fractionated by chromatography to give 8-ethyl-thienyl[3',4':6,5]dipyrido[2,3-b:3',2'-f]azepine mp 140-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[NH4+].[Cl-]>[Fe]>[NH2:17][C:4]1[CH:3]=[C:2]([CH3:1])[CH:16]=[CH:15][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: Cc1ccc(C(=O)Nc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(C(=O)Nc2ccccc2)c(N)c1

Procedure:
The product from Example 95b was reduced with Fe and NH4Cl following the procedure from Example 237E to give the title compound.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[N:5][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1.Br[C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:23]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[CH2:36][CH2:35]3)[CH:22]=1>>[N:12]1([CH2:11][CH2:10][O:9][C:6]2[N:5]=[CH:4][C:3]([C:21]3[O:25][C:24]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[C:23]([C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[C:37](=[O:41])[CH2:36][CH2:35]5)[CH:22]=3)=[CH:8][N:7]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(-c3cc(Br)oc3-c3ccncc3)ccc21
Reactant: C[Sn](C)(C)c1cnc(OCCN2CCOCC2)nc1
Product: O=C1CCc2cc(-c3cc(-c4cnc(OCCN5CCOCC5)nc4)oc3-c3ccncc3)ccc21
Yield: 48 %

Procedure:
The title compound (0.11 g, 48%) was prepared from the product of Step 2 and the product from Example 5 Step 9 using the method of Example 5 Step 10; MS(ES+) m/e 483 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:25][CH2:24][C:14]4([CH2:23][CH2:22][C:17]5(OCC[O:18]5)[CH2:16][CH2:15]4)[C:13]3=[O:26])=[CH:8][CH:7]=2)[CH2:3]1.Cl.CCOC(C)=O>CCCCCCC>[F:27][C:2]1([F:1])[CH2:3][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:25][CH2:24][C:14]4([CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]4)[C:13]3=[O:26])=[CH:8][CH:7]=2)[CH2:5]1
Reactant: O=C1N(c2ccc(C3CC(F)(F)C3)cc2)CCC12CCC1(CC2)OCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1CCC2(CC1)CCN(c1ccc(C3CC(F)(F)C3)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 133 step 5 from 10-[4-(3,3-Difluoro-cyclobutyl)-phenyl]-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 340, step 2) by treatment with 2M HCl. White solid (89%). Rf 0.53 (4:1 AcOEt:heptane)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([O:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][O:55]1)[CH2:15][N:16]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:22]([OH:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C@@H](CCCCN(C(OCC1C=CC=CC=1)=O)C[C@@H](OC1CCCCO1)CCNC(OCC1C=CC=CC=1)=O)C(O)=O.C1C(=O)N(OC(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)C(=O)C1.C([O-])([O-])=O.[Na+].[Na+]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@H:14]([O:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][O:55]1)[CH2:15][N:16]([C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44])[CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:22]([OH:24])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC[C@H](CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OCc1ccccc1)OC1CCCCO1)OCc1ccccc1
Agent: N[C@@H](CCCCN(C[C@H](CCNC(=O)OCc1ccccc1)OC1CCCCO1)C(=O)OCc1ccccc1)C(=O)O
Agent: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Product: O=C(NCC[C@@H](CN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OCc1ccccc1)OC1CCCCO1)OCc1ccccc1
Yield: 55 %

Procedure:
According to the method described for the preparation of 11a, 18b (26 mg, 44 μmol) was reacted with 9-fluorenylmethyl N-succinimidyl carbonate (22 mg, 66 μmol) and Na2CO3 (9 mg, 88 μmol) to give 11b (20 mg, 55%) as a colorless oil: 1H NMR δ 1.14-1.96 (m, 14H), 3.04-3.55 (m, 6H), 3.64-3.98 (m, 3H), 4.14 (m, 1H), 4.20 (t, 1H, J=6.9), 4.34 (d, 2H, J=6.9), 4.38-4.61 (m, 1H), 5.05 (s, 2H), 5.09 (s, 2H), 7.20-7.42 (m, 14H), 7.65 (m, 2H), 7.78 (d, 2H, J=7.4); HRMS m/z calcd for C46H54N3O10 808.3809, found 808.3839. Anal. calcd. for C46H53N3O10: C68.38, H 6.61, N 5.20. Found: C 68.26, H 6.69, N 5.13.