Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([O:35][C@@H:36]([CH2:46][O:47][C@H:48]([CH3:61])[CH2:49][O:50][Si](C(C)C)(C(C)C)C(C)C)[C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[O:38])=[C:29]2[CH:28]=[N:27]1>O1CCCC1>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2=[N:31][CH:32]=[N:33][C:34]([O:35][C@@H:36]([CH2:46][O:47][C@H:48]([CH3:61])[CH2:49][OH:50])[C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)=[O:38])=[C:29]2[CH:28]=[N:27]1
Reactant: CC(C)[Si](OC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccccn1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](CO)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A solution of tetrabutylammonium fluoride (1M in THF) (0.526 mL, 0.53 mmol) was added in one portion to a stirred solution of (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(pyridin-2-yl)-3-((R)-1-(triisopropylsilyloxy)propan-2-yloxy)propanamide (0.329 g, 0.53 mmol) (Intermediate AQ3) in tetrahydrofuran (15 mL). The resulting solution was stirred at ambient temperature for 30 minutes. The reaction mixture was quenched with saturated NH4Cl (10 mL), and diluted with water (20 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (50 mL), The combined organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane to afford the product (0.247 g, 100%). 1H NMR: (400 MHz, CDCl3) δ 1.16-1.19 (3H, m), 3.45-3.85 (4H, m), 4.1-4.31 (2H, m), 6.06-6.09 (1H, m), 7.05-7.09 (1H, m), 7.46-7.63 (4H, m), 7.73-7.75 (1H, m), 8.17 (1H, d), 8.26-8.28 (1H, m), 8.43 (1H, d), 8.60 (1H, s), 9.23 (1H, s); m/z (ES+) (M+H)+=469.24; HPLC tR=1.91 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:21][C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl.CO.[Pd]>[C:16]([O:15][C:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])[CH2:21][C:22]([OH:24])=[O:23])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCOCCN(CCOCCO)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOCCN(CCOCCO)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.6 %

Procedure:
To a solution of benzyl 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethyl-[2-(2-hydroxyethoxyl)ethyl]amino]acetate (19) (1.25 g, 2.84 mmol) in DCM (4 mL) and methanol (6 mL) was added palladium (10%) on activated carbon (100 mg). The resulting mixture was placed under an atmosphere of hydrogen. The mixture was stirred at room temperature overnight and then filtered through Celite. The Celite was washed with methanol (2×20 mL) and the combined filtrates were concentrated at reduced pressure to give 1.20 g of 20. 13C NMR (CD3OD, 125 MHz) δ 170.5, 156.2, 79.3, 72.8, 70.6, 66.8, 61.4, 55.2, 55.0, 40.3, 28.5. ESMS (C15H31N2O7) [M+H]+ calc. 351.2131. found 351.2127.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][CH:23]=[C:22]([C:25]([OH:27])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3][CH2:2]1.[C:28]([O:32][C:33](=[O:42])[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([NH2:41])[CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33](=[O:42])[NH:34][C@H:35]1[CH2:36][CH2:37][C@H:38]([NH:41][C:25]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[C:9]5[O:13][CH2:12][O:11][C:10]=5[CH:14]=[CH:15][C:7]=4[O:6][CH2:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)[C:17]=3[NH:24][CH:23]=2)=[O:27])[CH2:39][CH2:40]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CCC4)ccc4c3OCO4)ncnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CCC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclobutylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A68) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Br:12]Br>O1CCOCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][C:3]=1[OH:11]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: C1COCCO1
Product: Nc1c(O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.8 %

Procedure:
As shown by scheme (CLX), to a solution of 2-amino-3-nitrophenol 44 (10 g, 65 mmol) in anhydrous 1,4-dioxane (1 L) was added bromine (12.5 g, 78 mmol). The mixture was stirred at room temperature overnight. The solid was collected by filtration, washed with dioxane and dried. 2-amino-5-bromo-3-nitrophenol 45 (18 g, 90%) was obtained as its HBr salt in a form of a yellow solid. 1H NMR (DMSO-d6): δ 6.28 (br, 2H); 6.99 (d, J=2.2 Hz, 1H); 7.57 (d, J=2.1 Hz, 1H). MS (ESI+): m/z=234. Compound 45 (6 g, 19.1 mmol) was converted into compound 46 by using a method that was analogous to that used to synthesize compound 27, as shown on scheme (CXLI). Hydrogenation of compound 46 affords compound 47 (3.1 g, 67%) as a red solid.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[CH:7]=1)=[O:2].[C:11](N1C=CN=C1)([N:13]1C=CN=[CH:14]1)=O.CNC>O1CCCC1>[CH3:11][N:13]([C:8]([C:6]1[CH:7]=[C:3]([CH:1]=[O:2])[S:4][CH:5]=1)=[O:10])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1cc(C(=O)O)cs1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1csc(C=O)c1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-formyl-4-thiophenecarboxylic acid (prepared according to Gronowitz, S., et al., Arkiv. for Kemi. 21:265 (1963)) (1.24 g, 7.94 mmoles) in 50 ml of tetrahydrofuran was added 1,1'-carbonyldiimidazole (1.80 g, 11.10 mmoles) the solution stirred under dry argon for 11/2 hours and treated with excess gaseous dimethylamine. The solution was concentrated in vacuo to an oil which was dissolved in ethyl acetate (60 ml) and extracted with 1N hydrochloric acid (1×30 ml) followed by 5% sodium bicarbonate (1×30 ml). Each of the aqueous extracts was backwashed with ethyl acetate (2×50 ml) and the combined organic layers were dried (magnesium sulfate). Concentration in vacuo furnished a tan solid (1.15 g, 79%). EIMS (m/z): 183 (M+, 31%), 155 (M+ -CO, 38%), 139 (M+ -(CH3)2N, base) and 111 (M+ -(CH3) 2 NCO, 25%); 1HNMR (DMSO-d6) delta, 9.89 (1H, d, J=1.4Hz), 7.89 (1H, dd, J=1.5, 1.4Hz), 7.86 (1H, d, J=1.5Hz), 3.08 (6H, s). This material was used directly without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[CH2:5][N:6]=[CH:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][NH:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH3:15]
Reactant: CCOC(CN=Cc1cccs1)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNCc1cccs1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
2,2-Diethoxy-N-(thiophen-2-ylmethylene)ethaneamine (100 g) prepared in the step 1 was dissolved in 500 mL of dry ethanol, then 18.3 g of sodium borohydride was slowly added thereto little by little at room temperature and the mixture was stirred overnight at room temperature. The solvent was evaporated from the reaction solution in vacuo and the residue was poured over 300 mL of a 10% aqueous solution of acetic acid. The resulting aqueous solution was washed with diethyl ether, neutralized with 10% aqueous ammonia and subjected to extraction with diethyl ether. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 72.5 g of the objective compound as colorless liquid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH2:6]Br.C(Br)CCCC.ClCCCC(=O)CCCCC(F)(F)F.ClCCCC(O)CCCCC(F)(F)F.ClCCCC(OC(=O)C)CCCCC(F)(F)F.C(OC(C(C(=O)C)CCCC1C=CC(C(OCC)=O)=CC=1)=O)(C)(C)C.[C:86]([C:89](C(OC(C)(C)C)=O)([CH2:104][CH2:105][CH2:106][CH:107]([O:116]C(=O)C)CCCCC(F)(F)F)[CH2:90][CH2:91][CH2:92][C:93]1[CH:103]=[CH:102][C:96]([C:97]([O:99]CC)=[O:98])=[CH:95][CH:94]=1)(=[O:88])[CH3:87].C(C(CCCC(OC(=O)C)CCCCC(F)(F)F)CCCC1C=CC(C(OCC)=O)=CC=1)(=O)C>>[C:86]([CH:89]([CH2:104][CH2:105][CH2:106][CH:107]([OH:116])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])[CH2:90][CH2:91][CH2:92][C:93]1[CH:94]=[CH:95][C:96]([C:97]([OH:99])=[O:98])=[CH:102][CH:103]=1)(=[O:88])[CH3:87]
Reactant: FC(F)(F)CCCCBr
Reactant: CCOC(=O)c1ccc(CCCC(CCCC(CCCCC(F)(F)F)OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C)cc1
Agent: CC(=O)OC(CCCCl)CCCCC(F)(F)F
Agent: CCOC(=O)c1ccc(CCCC(C(C)=O)C(=O)OC(C)(C)C)cc1
Agent: CCOC(=O)c1ccc(CCCC(CCCC(CCCCC(F)(F)F)OC(C)=O)C(C)=O)cc1
Solvent: CCCCCBr
Product: CC(=O)C(CCCc1ccc(C(=O)O)cc1)CCCC(O)CCCCC(F)(F)F

Procedure:
The synthesis of this compound is carried out as described in Example 1, except that in Step B(1) an equivalent amount of 1,1,1-trifluoro-5-bromopentane is substituted for amyl bromide. The product of Step B(1) thus becomes 1-chloro-9,9,9-trifluoro-4-nonanone. Subsequent steps afford in order: Step B(2), 1-chloro-9,9,9-trifluoro-4-nonanol; Step B(3), 1-chloro-4-acetoxy-9,9,9-trifluorononane; Step C, ethyl 4-(4-tert-butoxycarbonyl-5-oxohexyl)benzoate; Step D, ethyl 4-(4-acetyl-4-tert-butoxycarbonyl-8-acetoxy-13,13,13-trifluorotridecyl)benzoate (by substituting 1-chloro-4-acetoxy-9,9,9-trifluorononane for 1-chloro-4-acetoxynonane); Step E, ethyl 4-(4-acetyl-8-acetoxy-13,13,13-trifluorotridecyl)benzoate; and Step F, 4-(4-acetyl-8-hydroxy-13,13,13-trifluorotridecyl)benzoic acid, obtained as a viscous yellow oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]#[N:14])=[CH:7][CH:6]=[CH:5][C:4]1=2)=O.[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][NH2:24])([CH3:18])([CH3:17])[CH3:16].CC(O)=O.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.O>[C:13]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:3]2[CH2:1][NH:24][CH2:23][CH2:22][NH:21][C:20](=[O:25])[O:19][C:15]([CH3:18])([CH3:16])[CH3:17])#[N:14]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: N#Cc1cccc2c1CCCC2C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNCC1CCCc2c(C#N)cccc21
Reaction time: 2.5 h

Procedure:
A solution of 5-Formyl-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (0.30 g, 1.6 mmol) in MeOH (8 mL) was added (2-amino-ethyl)-carbamic acid tert-butyl ester (0.26 g, 1.6 mol) in MeOH (8 mL), followed by AcOH (0.29 g, 4.8 mmol) and NaBH3CN (0.20 g, 3.2 mmol). The reaction mixture was stirred 2-3 h, and then water (20 mL) and DCM (20 mL) was added. Extracted with DCM, and the organic layers were dried over anhydrous Na2SO4, evaporate to give the crude product, which was purified by column to give the title compound. MS m/z: 330 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][CH2:17][OH:18])=[S:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(N=C=S)c1
Reactant: NCCCO
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(NC(=S)NCCCO)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a stirred solution of 24 parts of 1-chloro-2-isothiocyanato-4-nitrobenzene in 200 parts of ethanol 95% are added dropwise 9 parts of 3-amino-1-propanol at a temperature below 20° C. Upon completion, stirring is continued for 30 minutes at room temperature. The reaction mixture is evaporated. The residue is crystallized from acetonitrile. The product is filtered off and dried, yielding 23 parts (72%) of N-(2-chloro-5-nitrophenyl)-N'-(3-hydroxypropyl)thiourea; mp. 126.8° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([CH3:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:23][C:24]([F:38])([F:37])[CH2:25][C:26]1[S:30][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:28][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([CH3:20])([CH3:21])[C:16]([F:18])([F:17])[F:19])=[C:9]([C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:30][C:26]([CH2:25][C:24]([F:38])([F:23])[F:37])=[CH:27][N:28]=3)[CH2:32][CH2:33]2)=[O:12])[CH:13]=1)(=[O:4])=[O:3]
Reactant: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: FC(F)(F)Cc1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(CC(F)(F)F)s2)CC1)C(F)(F)F
Yield: 27 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzoic acid (Example A14) and 1-[5-(2,2,2-trifluoro-ethyl)-thiazol-2-yl]-piperazine hydrochloride (Example 69(e)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 27%). MS (m/e): 560.3 (M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38]>O1CCOCC1>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37]([NH:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]1=[O:26])=[O:38]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2N)NC(=O)CO3)c1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2NC(=O)c2ccc4ccccc4c2)NC(=O)CO3)c1=O

Procedure:
3-[5-Amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-1-methyl-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (0.37 g) and 2-naphthoyl chloride (0.21 g) were mixed in dioxane (15 ml) and the mixture was refluxed for 6 hr. After evaporation of solvent, the residue was recrystallized from toluene (0.20 g).
Reaction SMILES: C(O)=O.[C:4]1([CH:10]2[CH:17]3[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:19][C:11]2([CH2:20][CH:21]([CH3:24])[NH:22][CH3:23])[CH2:12]4)[CH2:16]3)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25]=O.[ClH:27]>CCOCC.O>[ClH:27].[C:4]1([CH:10]2[CH:17]3[CH2:16][CH:15]4[CH2:14][CH:13]([CH2:12][C:11]2([CH2:20][CH:21]([CH3:24])[N:22]([CH3:25])[CH3:23])[CH2:19]4)[CH2:18]3)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=O
Reactant: CNC(C)CC12CC3CC(CC(C3)C1c1ccccc1)C2
Agent: Cl
Solvent: O
Solvent: O=CO
Solvent: CCOCC
Product: CC(CC12CC3CC(CC(C3)C1c1ccccc1)C2)N(C)C
Reaction time: 8 h

Procedure:
Formic acid (4.5 ml.) and water (0.5 ml.) were added to the 2-phenyl-N,α-dimethyl-1-adamantaneethylamine (1.0 g.) followed by a 40 percent formaldehyde solution (5 ml.). The mixture was heated on a boiling water bath for seven hours and then allowed to stand overnight. The aqueous solvents were removed in vacuo and the residue treated with dilute hydrochloric acid. Excess acid was removed in vacuo and the oily residue extracted between 3N sodium hydroxide and ether. The organic phase was washed twice with water and dried over magnesium sulfate. The ether was then removed in vacuo to leave 1.1 g. of the base as an oil. The base was dissolved in dry ether, and ethereal hydrochloric acid was added in excess. The resulting precipitate was filtered off and dried in vacuo, and then crystallized from an ethanol-ether mixture to yield 0.3 g. of crystals. Recrystallization from an ethanol-ether mixture yielded 2-phenyl-N,N,α-trimethyl-1-adamantaneethylamine hydrochloride, m.p., 186° -90° C.
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+].CCOCC>O1CCCC1>[ClH:18].[N:1]1([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCc3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1ccc(N2CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.06 g (54.8 mmole) of 4-(1-indolinyl)benzonitrile of Example 2a in 62 ml tetrahydrofuran (THF) was added dropwise to a rapidly stirred ice cold solution of BH3 in THF (181 ml of 0.93 M solution, 3.07 equiv. 168.4 mmole) under nitrogen. After heating at reflux for 1.5 hours, the solution was permitted to cool to room temperature and stand overnight. The ice cold reaction mixture was then treated dropwise with 6 M aq. HCl (100 ml), heated at reflux for 40 minutes, cooled to 0° C., and made basic using solid NaOH. The resulting aqueous phase was extracted with ether and the combined organic portions (100 ml total) were washed with water (300 ml), twice with brine (300 ml portions) dried (Na2SO4) and concentrated to afford 13.2 g of crude free base. A solution of 7.5 g (33.4 mmole) of crude free base in 200 ml 1:1 ethanol-ether was treated with 50 ml of ethanolic HCl. 200 ml dry ether was added and the resulting solid was filtered, washed with dry ether, and dried thus giving 5.9 g (67.7%) of crude product. Recrystallization from hot ethanol-ether (charcoal) afforded 2.98 g of pure 4-(1-indolinyl)benzenemethanamine hydrochloride, m.p. 251.5°-252.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH2:28][CH2:29][OH:30])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[CH:15][CH:14]=1)#[N:12].C(N(CC)CC)C>ClCCl>[C:11]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][N:22]([CH2:28][CH:29]=[O:30])[C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[CH:17][CH:18]=1)#[N:12]
Reactant: CN(C)C(=O)N(CCO)CCCc1ccc(C#N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(CC=O)CCCc1ccc(C#N)cc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
Oxalyl chloride (4.84 g, 0.038 mol) was added dropwise to a stirred solution of DMSO (5.9 g, 0.0763 mol) and dichloromethane (100 mL) at −78° C. After 15 min at the same temperature, 1-[3-(4-cyanophenyl)propyl]-1-(2-hydroxyethyl)-3,3-dimethylurea (7 g, 0.0254 mol) in dichloromethane was added and stirring continued for 3 h under a nitrogen atmosphere. Triethylamine (12.8 g, 0.127 mol) was added (dropwise), and the reaction mixture was then warmed slowly to −30° C. The reaction mixture was quenched with 10% citric acid (aq.) and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to yield 6.5 g of the crude title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](F)[C:17]=1[N+:24]([O-])=O)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:24])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)ccc3N)cccc2[nH]1
Reaction time: 2 h

Procedure:
142 (1.6 g, 4.734 mmol) is dissolved in 250 ml of ethyl acetate and, after addition of Pd—C (200 mg), the mixture is hydrogenated at room temperature for 2 hours. The mixture is filtrated over celite to remove the catalyst and evaporated.
Reaction SMILES: [C:1]([CH2:3][C@:4]1([C:30]([O:32]C)=O)[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15]CC3C=CC=CC=3)=[CH:11][CH:10]=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])#[N:2]>CO.[Ni]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:6]2[CH2:7][CH2:8][C@@:4]3([CH2:3][CH2:1][NH:2][C:30]3=[O:32])[N:5]2[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@]1(CC#N)CC[C@@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](c2ccc(O)cc2)CC[C@@]12CCNC2=O
Reaction time: 6 h
Yield: 35.2 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5S)-2-(cyanomethyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D77, 500 mg, 1.11 mmol) in methanol (30 ml) was added Raney Nickel (slurry in water, 1 spatula) and the mixture was stirred under a hydrogen atmosphere (6 atm) for 6 hours. The catalyst was filtered off, the solvent removed under reduced pressure, and the solid residue was treated two times with toluene and dried under vacuum. The dry white solid obtained was refluxed in methanol (30 ml) for six hours until cyclization was complete. The solvent was removed under reduced pressure and the crude material purified by chromatography on silica gel using dichloromethane/methanol (1:0 to 92:8) to afford the title compound as a white solid (130 mg, 35%); Rt (HPLC): 3.89 min; Rf (dichloromethane/methanol=9:1): 0.41; MS: (ES/+) m/z: 665 [2M+Na+], 355 [M+Na+]; C18H24N2O4 requires 332; 1H NMR (400 MHz, DMSO-d6) δ(ppm): 9.11 (s, 1H); 7.76 and 7.66 (s, s, 1H); 7.43 (dd, 2H); 6.66 (dd, 2H); 4.81-4.70 (m, 1H); 3.29-3.20 (m, 1H); 3.19-3.09 (m, 1H); 2.47-2.20 (m, 2H); 2.08-1.85 (m, 2H); 1.84-1.74 (m, 1H); 1.68-1.52 (m, 1H); 1.33 and 1.08 (s, s, 9H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]([C@@H:12]([CH2:21][CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:26]I>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([C@@H:12]([CH2:21][CH2:22][CH3:23])[CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][CH3:26])[CH2:16][CH2:15]2)[CH3:11])=[O:9])=[CH:24][CH:25]=1
Reactant: CCC[C@@H](CN1CCC(O)CC1)N(C)C(=O)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@@H](CN1CCC(OC)CC1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 50.9 %

Procedure:
NaH (21.24 mg, 0.89 mmol) was added to a solution of (S)-4-chloro-N-(1-(4-hydroxypiperidin-1-yl)pentan-2-yl)-N-methylbenzamide (Example 44) (200 mg, 0.59 mmol) in dry THF (10 mL) at room temperature under N2. After 5 min was MeI (0.037 mL, 0.59 mmol) added. The reaction was stirred overnight and was then quenched by addition of NH3 saturated H2O (2 mL). The resulting solution was evaporated and the remainder was dissolved in EtOAc and poured on an SCX-2 column (5 g). The column was washed with MeOH and the product was eluted by NH3 saturated MeOH. The crude product was purified by preparative HPLC to yield the title product (106 mg, 51.0%). 1H NMR (600 MHz, DMSO-d6) δ 0.78, 0.91, 1.05-1.51, 1.70-1.84, 1.91-2.03, 2.09-2.13, 2.17-2.23, 2.33-2.39, 2.41-2.54, 2.58-2.64, 2.76, 2.82, 3.12, 3.19-3.22, 3.53-3.59, 4.71-4.79, 7.31-7.35, 7.36-7.40, 7.47-7.53. HRMS (M+H)+: calculated 353.1996. found 353.2006.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C@H:23]3[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)[C:17](=[O:24])[NH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>>[CH:4]1([O:5][C:6]2[CH:7]=[C:8]([C:14]3[C@H:23]4[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]4)[C:17](=[O:24])[NH:16][N:15]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:10][CH2:11][CH2:6][CH2:7]1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: NN
Solvent: O
Product: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound D (see starting compounds) and hydrazine hydrate as described for compound 1. M.p. 175-176° C.