Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([OH:16])=O)[N:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[C:38]12([NH2:48])[CH2:47][CH:42]3[CH2:43][CH:44]([CH2:46][CH:40]([CH2:41]3)[CH2:39]1)[CH2:45]2>CN(C=O)C.C(OCC)(=O)C>[C:38]12([NH:48][C:14]([C:7]3[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=34)=[O:16])[CH2:45][CH:44]3[CH2:43][CH:42]([CH2:41][CH:40]([CH2:46]3)[CH2:39]1)[CH2:47]2
Reactant: CCCCc1nc(C(=O)O)c2ccccn12
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C(=O)NC23CC4CC(CC(C4)C2)C3)c2ccccn12
Reaction time: 0.17 h
Yield: 79.8 %

Procedure:
To a solution of 3-butyl-imidazo[1,5-a]pyridine-1-carboxylic acid (150 mg, 0.56 mmol) in DMF (5 mL) was added EDC (161 mg, 0.84 mmol), HOBt, (90 mg, 0.67 mmol) and Et3N (0.23 mL, 1.68 mmol). The mixture was allowed to stir for 10 min. and adamantylamine (93 mg, 0.62 mmol) was added. The mixture was stirred for 15 h then diluted with ethyl acetate (30 mL) and washed with water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (157 mg, 80%). 1H NMR (DMSO-d6) δ 8.31 (1H), 8.02 (1H), 7.04 (1H), 6.93 (1H), 6.81 (1H), 2.99 (2H), 2.08 (9H), 1.67 (8H), 1.38 (2H), 0.92 (3H); m/z (M+H)=352.1.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6]1)#[CH:4].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:15][C:13](=[O:14])[CH2:12][O:10][C:5]1([C:3]#[CH:4])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C#CC1(O)CCCC1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CC1(OCC(=O)OC)CCCC1
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of sodium hydride (60% dispersion in mineral oil, 1.5 g, 38 mmol) in tetrahydrofuran (10 mL) at 0 C. under nitrogen was treated with a solution of 1-ethynylcyclopentanol (5.0 g, 45 mmol) in tetrahydrofuran (20 mL) over 15 minutes. After stirring at 0 C. for 1 hour, the mixture was treated with methyl bromoacetate (5.4 mL, 56 mmol). after stirring at ambient temperature for 16 hours, the mixture was treated with 2M HCl (25 mL) and then treated with ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, concentrated and used without purification in the next step.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].Cl.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH2:34].OCCCCNC(=O)C1C=CC=CC=1>>[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH:26]1[NH:34][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]2[CH2:13][CH2:12][C:8]3[N:9]=[CH:10][S:11][C:7]=3[CH2:6]2)=[CH:16][CH:17]=1
Reactant: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=C(NCCCCO)c1ccccc1
Product: CCCN(Cc1ccc(C(=O)NC2Cc3ccccc3C2)cc1)C1CCc2ncsc2C1
Yield: 58 %

Procedure:
Compound 44 is prepared from 42C and indan-2-ylamine hydrochloride as described for 1D.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23](=[O:26])[CH2:24]Cl)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:29][NH2:30])[OH:28].CCOC(C)=O>C(OC(C)C)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23](=[O:26])[CH2:24][NH:30][CH2:29][CH2:27][OH:28])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=C(CCl)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Product: O=C(CNCCO)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Temperature: 55 °C

Procedure:
To a solution of the product from Step C (1.07 g, 2.66 mmol) in 5 mL of isopropyl acetate was added ethanolamine (0.643 mL, 10.6 mmol). The reaction was warmed to 55° C. for 2 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown foam.
Reaction SMILES: Cl.[NH:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:19](=[CH:20][CH:21]=2)[O:18][C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][C:10]3=[O:22])=[N:5][N:4]=[N:3]1.[CH3:23][C:24]1[C:25]2[CH:37]=[C:36]([C:38](O)=[O:39])[S:35][C:26]=2[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:28]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CCN(CC)CC.CN(C=O)C.O.CCOCC.C(Cl)(Cl)Cl>[CH3:23][C:24]1[C:25]2[CH:37]=[C:36]([C:38]([N:15]3[CH2:16][CH2:17][C:12]4([CH2:11][C:10](=[O:22])[C:9]5[C:19](=[CH:20][CH:21]=[C:7]([C:6]6[NH:2][N:3]=[N:4][N:5]=6)[CH:8]=5)[O:18]4)[CH2:13][CH2:14]3)=[O:39])[S:35][C:26]=2[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:28]=1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: Cc1nn(-c2ccccn2)c2sc(C(=O)O)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccccn2)c2sc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5nnn[nH]5)ccc3O4)cc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
6-(Tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (232 mg), 3-methyl-1-pyridin-2-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (155 mg), EDCI (153 mg) and HOBT (122 mg) were suspended in Et3N (1 mL) and DMF (8 mL). The suspension was stirred at 80° C. for 1.5 hours under heat, then cooled to room temperature, and chloroform (1.8 mL) was added thereto. Its pH was adjusted at 2.5 with 1 N HCl added thereto, and this was diluted with water, and Et2O was added thereto. The formed crystal was taken out through filtration, washed with water and Et2O—CHCl3, and dried in vacuum to obtain the title compound as a pale yellow powder. 1H-NMR (400 MHz, DMSO-d6): δ 8.53 (1H, d, J=4.4 Hz), 8.44 (1H, s), 8.25 (1H, d, J=8.5 Hz), 8.01 (1H, t, J=7.8 Hz), 7.90 (1H, d, J=8.5 Hz), 7.61 (1H, s), 7.37 (1H, d, J=8.8 Hz), 7.31 (1H, t, J=5.9 Hz), 6.44 (2H, s), 4.20 (2H, d, J=12.9 Hz), 3.48 (2H, br s), 2.52 (3H, s), 2.06 (2H, d, J=13.7 Hz), 1.94-1.81 (2H, m). MS [M+H]+=527.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.Cl.[CH3:30][N:31]1[C:35]([CH:36]=O)=[N:34][C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=2)=[N:32]1.C(N(CC)CC)C.Cl>C(O)(C)C.O>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:36][C:35]3[N:31]([CH3:30])[N:32]=[C:33]([C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[N:39]=4)[N:34]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(-c2nc(C=O)n(C)n2)n1
Reactant: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(-c2nc(CC3=C(O)CC(CCc4ccc(C(C)(C)C#N)c(F)c4)(C4CCCC4)OC3=O)n(C)n2)n1
Temperature: 48.5 °C
Yield: 38 %

Procedure:
A solution of 2-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-2-methyl-propionitrile (1.0 g, 2.70 mmol, from step 3 of example A(84) in hot (50° C.) isopropanol (7 mL) was treated with (CH3)2NHBH3 (175 mg, 2.97 mmol, 1.1 equiv), then with a solution of 1-methyl-3-(6-methylpyridin-2-yl)-1H-1,2,4-triazole-5-carbaldehyde hydrochloride hydrate (762 mg, 2.97 mmol, 1.1 equiv, from Step 4 below) in isopropanol (4 mL) containing triethylamine (301 mg, 2.97 mmol, 1.1 equiv). The reaction mixture was stirred heated at 47-50° C. for 18 h. The reaction mixture was treated with 1.1 equiv of 1 M aqueous HCl and concentrated in vacuo to afford an oily resin. This was diluted with water and extracted with dichloromethane containing 10% methanol (3×30 mL). The extract was dried over Na2SO4, filtered, and concentrated. The residue was triturated with hot ethyl acetate/methylene chloride, filtered, washed with cold ether, and dried, affording 584 mg (38%) of the title product. 1H NMR (400 MHz, DMSO-d6): δ 1.36-1.71 (m, 14 H), 2.05 (m, 2 H), 2.48 (m, 1 H), 2.46 (s, 3 H), 2.63 (m, 3 H), 2.78 (d, J=17.9 Hz, 1 H), 3.67 (d, J=15.7 Hz, 1 H), 3.74 (d, J=15.7 Hz, 1 H), 3.91 (s, 3 H), 6.99 (d, J=8.1 Hz, 1 H), 7.10-7.20 (m, 3 H), 7.57 (m, 2 H), 11.22 (s, 1 H). LC-MS (APCI) calcd for C32H36FN5O3: 557.28, found (M+H+): 558.40 m/z.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]2[CH:16]=[CH:17][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH2:30][CH3:31])[CH2:24][O:23][C:22]3=[O:28])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2)CC1
Reactant: CCI
Product: CCOC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 75.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-4-[4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (2.43 g) described in Preparation Example 163 and ethyl iodide (1.12 g), the title compound (1.97 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].S(Cl)(Cl)=O.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>C1(C)C=CC=CC=1>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]([CH3:12])[CH:5]=3)=[O:9])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C#N
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C#N
Reaction time: 18 h

Procedure:
A solution of 4-cyano-3-methylbenzoic acid from Example C (1.2 g, 7.5 mmol) and thionyl chloride (3.6 ml, 54 mmol) in toluene (20 ml) was heated at reflux for 2 h. The mixture was evaporated and azeotroped with toluene. The residue was dissolved in dichloromethane, 10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine (1.4 g, 7.5 mmol) was added and the mixture stirred for 18 h. The mixture was evaporated and the residue purified by flash chromatography on silica (EtOAc:pet ether, 30:70 to 80:20) to give a cream solid, yield 1.5 g, 63%.
Reaction SMILES: FC(F)(F)C([NH:5][C@H:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=O.[OH-].[Na+]>C1COCC1.CO.O>[N+:16]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][C@H:6]2[NH2:5])=[CH:11][C:12]=1[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([O-:18])=[O:17]
Reactant: O=C(N[C@@H]1CCCc2cc(CN3CCCCC3)c([N+](=O)[O-])cc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CCCc2cc(CN3CCCCC3)c([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 115.2 %

Procedure:
A solution of (R)-2,2,2-trifluoro-N-(7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (230 mg, 0.6 mmol) and NaOH (108 mg, 2.7 mmol) in a mixed solvent (THF/MeOH/H2O=5 mL/5 mL/1 mL) was heated at 70° C. for 3 h. After cooling to RT, the solvent was evaporated to dryness and the residue was directly loaded on column chomatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:15 to 100:20) to give (R)-7-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (200 mg) as a white solid. Similarly (R)-(1-nitro-5-(2,2,2-trifluoroacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl acetate was converted to (R)-5-nitro-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-1-amine according to the above sequence of reactions.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Br[C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:27][C:21]([O:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=2)=[CH:18][CH:17]=1)([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(C)=O)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-Methyl-2-[4-(2-acetamido-ethyl)-biphenyl-4'-oxy]-propionate was prepared from 4-(2-acetamido-ethyl)-4'-hydroxybiphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 20% of theory; m.p. <20° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH2:29][CH2:28][CH2:27][N:26]3[S:23]([C:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=3[O:15][CH3:14])(=[O:25])=[O:24])=[CH:31][CH:32]=2)=[O:37])=[CH:8][CH:7]=1)[CH3:5]
Reactant: COC(=O)C(C)c1ccc(N)cc1
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Product: COC(=O)C(C)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using 2-(4-amino-phenyl)-propionic acid methyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded 2-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-propionic acid methyl ester, which was hydrolyzed to 2-(4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-phenyl)-propionic acid in step 4, MS (ISP): m/e=526.2 (M−H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13]C)=[O:12])[CH2:3][CH2:2]1.[Li+].[OH-]>CO.O>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])[CH2:5][CH2:6]1
Reactant: COC(=O)c1cccc(CN2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(CN2CCOCC2)c1
Temperature: 60 °C
Yield: 42.4 %

Procedure:
To a solution of methyl 3-(morpholinomethyl)benzoate (150 mg, 0.64 mmol) in MeOH (2 mL) and water (2 mL) was added LiOH (55 mg, 1.31 mmol) at 20° C. The mixture was heated to 60° C. for 1 h. The reaction solution was concentrated and purified via prep-HPLC to give the title compound (60 mg, Yield 42.5%). LCMS (m/z): 222 (M+1).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.O[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([CH3:39])[CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:30]2[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[C:32]([CH3:39])[CH:31]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)c1ccc(O)cc1C
Product: CC(=O)c1ccc(OCCCc2c[nH]cn2)cc1C

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (4-hydroxy-2-methylphenyl)ethanone are treated as described in Example 56, but isolated in the form of the free base.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7])C.[OH-].[Na+]>C(O)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:5]([C:6]([F:7])([F:8])[F:9])([C:10]([F:11])([F:12])[F:13])[C:4]([OH:23])=[O:3])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl-2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate (3.65 g.), N-aqueous sodium hydroxide (100 ml.) and ethanol (50 ml.) is stirred at ambient temperature for 2 days, and then evaporated in vacuo. Water is added, and the mixture is washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is dried with sodium sulphate, evaporated, and the residue is crystallised from light petroleum (b.p. 40°-60° C.) to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionic acid, m.p. 98°-99° C. (1.42 g.).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[CH:25]5[CH2:26][CH2:27][CH:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:11][C:6]=2[O:5][CH2:4]1.C(N(CC)CC)C.[CH3:45][C:46]([CH3:52])([CH2:50][OH:51])[C:47](O)=[O:48].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3([CH2:18][CH2:19][N:20]4[C@H:25]5[CH2:26][CH2:27][C@@H:21]4[CH2:22][CH:23]([N:28]4[C:32]6[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=6[N:30]=[C:29]4[CH3:37])[CH2:24]5)[CH2:13][CH2:14][N:15]([C:47](=[O:48])[C:46]([CH3:52])([CH3:45])[CH2:50][OH:51])[CH2:16][CH2:17]3)=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CC(C)(CO)C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccc3c(c2)OCO3)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccc3c(c2)OCO3)CCN(C(=O)C(C)(C)CO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A mixture of 1-(8-{2-[4-(1,3-benzodioxol-5-yl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (0.20 g, 0.39 mmol), triethylamine (0.17 mL, 1.25 mmol) and 2,2-dimethyl-3-hydroxypropionic acid (46 mg, 0.39 mmol) in dimethylformamide (1.25 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (163 mg, 0.43 mmol) and the resulting mixture was stirred for 1 h at rt. The mixture was diluted with water and the resulting gummy precipitate was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, with water, dried and purified by chromatography on silica gel eluting with a dichloromethane to methanol-dichloromethane 1:9 gradient to give 3-(4-(1,3-benzodioxol-5-yl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)-2,2-dimethyl-3-oxopropan-1-ol as a solid (0.13 g, 59%). 1H NMR (400 MHz, CDCl3) δ 7.66 (m, 1H), 7.29 (m, 1H), 7.15 (m, 2H), 6.80 (m, 2H), 6.73 (m, 1H), 5.97 (s, 2H), 4.62 (m, 1H), 3.92 (m, 2H), 3.75 (m, 1H), 3.46 (s, 2H), 3.26 (m, 4H), 2.57 (s, 3H), 2.38 (m, 2H), 2.14 (m, 2H), 1.91-2.00 (m, 6H), 1.70-1.78 (m, 4H), 1.64 (m, 2H), 1.25 (s, 6H). HRMS C34H44N4O4 m/z 573.3441 (M+H)Cal. 573.3428 (M+H)Obs..
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>>[CH2:20]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[CH:6]1)[CH:19]=[CH2:18]
Reactant: CC(C)(C)[O-]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [K+]
Solvent: C=CCBr
Product: C=CCn1cc(C[C@H]2CCCN2C)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a stirred solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (22.5 g, 76.8 mmol) in tetrahydroflran (132 ml) at 0° C. under a nitrogen atmosphere was added potassium tert-butoxide (9.47 g, 84.4 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown slurry was stirred at 0-5° C. for 30 min before allyl bromide (7.3 ml, 84.3 mmol) was added dropwise maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 1 hr period before being quenched into water (100 ml). The mixture was then extracted with ethyl acetate (3×25 ml) and the combined organic extracts were evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitle compound (19.94 g, 78%) as a golden oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:32]=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].Cl.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([CH:3]1[C:4]([C:10]2[CH:32]=[CH:31][C:13]3[N:14]=[C:15]([C:17]4[CH:30]=[CH:29][C:20]([O:21][CH2:22][CH:23]5[CH2:24][CH2:25][N:26]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:27][CH2:28]5)=[CH:19][CH:18]=4)[O:16][C:12]=3[CH:11]=2)=[N:5][NH:6][C:7](=[O:9])[CH2:8]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC4CCNCC4)cc3)oc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC4CCN(S(C)(=O)=O)CC4)cc3)oc2c1

Procedure:
15.5 mg (33 μmol) 4-{4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxymethyl}-piperidine as hydrochloride are stirred together with 2.6 μl (34 μmol) methanesulphonic acid chloride, 14 μl (100 μmol) triethylamine and 2 ml DCM at RT overnight within the next 4 days a further 14.4 μl methanesulphonic acid chloride and 24.5 μl triethylamine are added batchwise. Then the reaction mixture is combined with DCM and extracted 2× with 25 ml of water+3 drops of glacial acetic acid, 5% sodium carbonate solution and sat. saline solution. The solv. of the org. phase is evaporated off completely i.V. and the residue is stirred with cyclohexane/EA.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.Cl>>[NH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5](=[O:8])[NH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:25]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCNC(=O)OC(C)(C)C)c2n1
Agent: Cl
Product: NCCCNC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Temperature: 85 °C

Procedure:
A mixture of (R)-tert-butyl 3-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate (Example 141, 70 mg, 0.14 mmol) and HCl (4 N dioxane, 1.7 mL, 6.8 mmol) in a pressure reaction tube was heated at 85° C. for 12 hours then concentrated under reduced pressure. The crude material was purified by reverse-phase chromatography (5 to 40% acetonitrile/water) to yield the final product as white solid. LCMS (apci) m/z=400.1 (M+H).