Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].C(N(CC)CC)C.[I-].[C:39]([N:42]1[CH2:47][CH2:46][N:45]([C:48]([NH+]2C=CN(C)C2)=[O:49])[CH2:44][CH2:43]1)(=[O:41])[CH3:40]>C(Cl)Cl>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:48]([N:45]5[CH2:46][CH2:47][N:42]([C:39](=[O:41])[CH3:40])[CH2:43][CH2:44]5)=[O:49])[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: CC(=O)N1CCN(C(=O)[NH+]2C=CN(C)C2)CC1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)N5CCN(C(C)=O)CC5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 26 %

Procedure:
To a solution of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (25 mg, 0.063 mmol) and triethylamine (0.013 mL, 0.095 mmol) in CH2Cl2 (2 mL) was added 3-(4-acetyl-piperazine-1-carbonyl)-1-methyl-3H-imidazol-3-ium iodide (Intermediate 6) (15 mg, 0.063 mmol) and the mixture stirred at room temperature under argon for 18 h. Partitioned between CH2Cl2 (10 mL) and sat. NaHCO3(aq) (2 mL) and the organic layer was filtered through a phase separation tube and evaporated in vacuo. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions by elution through an Isolute SCX-2 cartridge, eluting with methanol, then with 2M ammonia in methanol. Basic fractions were concentrated in vacuo to give 1-(4-{(S)-3-[6-(6-Methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carbonyl}-piperazin-1-yl)-ethanone as a pale yellow powder (9 mg, 25% yield). 1H NMR (400 MHz, MeOH-d4, 298K) δ ppm 2.14 (s, 3H) 2.24-2.33 (m, 2H) 3.04 (t, 2H) 3.25-3.91 (m, 13H) 3.99 (s, 3H) 4.18 (s, 2H) 5.74-5.78 (m, 1H) 7.79 (d, 1H) 8.14 (d, 1H) 8.60 (s, 1H) LCMS: [M+H]+=550.2, Rt(1)=1.58 min.
Reaction SMILES: [CH2:1]([C:13]1[CH:14]=[C:15]([C:18]2[NH:19][C:20](=[O:44])[C:21]3[C:25]=2[C:24](=[O:26])[NH:23][C:22]=3[C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:31]=2)[S:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I[CH2:46][CH:47]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:48][CH2:49][CH2:50][CH3:51].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH2:48]([CH:47]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:46][N:23]1[C:22]([C:27]2[S:28][CH:29]=[C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH:31]=2)=[C:21]2[C:25](=[C:18]([C:15]3[S:16][CH:17]=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:14]=3)[N:19]([CH2:17][CH:13]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:14][CH2:15][CH2:18][CH2:25][CH2:21][CH3:20])[C:20]2=[O:44])[C:24]1=[O:26])[CH2:49][CH2:50][CH3:51]
Reactant: CCCCCCCCCCCCc1csc(C2=C3C(=O)NC(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2)c1
Reactant: CCCCCCC(CI)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCCCCCCCCCc1csc(C2=C3C(=O)N(CC(CCCC)CCCCCC)C(c4cc(CCCCCCCCCCCC)cs4)=C3C(=O)N2CC(CCCC)CCCCCC)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A 100 mL flask was charged with 3,6-bis-(4-dodecyl-thiophen-2-yl)-2,5-dihydro-pyrrolo[3,4-c]pyrrole-1,4-dione 4 (4.3 g, 6.75 mmol), 5-iodomethyl-undecane (6.22 g, 21.0 mmol), Cs2CO3 (7.82 g, 24.0 mmol) and then purged with argon for 10 minutes before 150 mL of dimethylformamide (DMF) was added. The mixture was heated at 60° C. for 36 hours, then at 90° C. for 8 hours, and cooled to room temperature before 200 mL of hexane was added. The organic layer was washed with water (200 mL, 3 times), then dried over anhydrous Na2SO4. Black solids were obtained after removal of the solvent and precipitation from methanol. The product was purified by column with dichloromethane/hexane (v/v: 2/1 with Rf=0.25) as the eluent and weighed 1.43 g (21.7% yield from 4-dodecyl-thiophene-2-carbonitrile 3) after drying.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][CH:8]1[C:15]([NH:17][C:18]1([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19]1)=[O:16].O[Li].O>>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9][CH:8]1[C:15]([NH:17][C:18]1([C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)[CH2:19][CH2:20]1)=[O:16]
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3cccc(C(F)(F)F)c3)CC4)CC2)cc1
Agent: [Li]O
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3cccc(C(F)(F)F)c3)CC4)CC2)cc1
Yield: 66.2 %

Procedure:
The title compound (E9) (39 mg) was prepared according to the general procedure for esters hydrolysis (Method D) starting from methyl 4-(1-(6-(3-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (single unknown enantiomer) (D125) (60.7 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[CH2:4][C:3]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:21]2[N:22]([CH:2]=1)[CH:23]=[CH:24][CH:25]=[CH:26]2
Reactant: c1ccc(Cc2ccccn2)cc1
Reactant: O=C(CBr)Cc1c(F)cccc1Cl
Solvent: CC(C)=O
Product: Fc1cccc(Cl)c1Cc1cn2ccccc2c1-c1ccccc1
Yield: 76.3 %

Procedure:
The compound of step 1 (1.17 g, 4.41 mmol) and 2-benzyl-pyridine (1.49 g, 8.82 mmol) were dissolved in acetone (15 ml) and the mixture was stirred under reflux overnight. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (DCM/MOH, 100:0, then 95:5) to give 1.13 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:26]=[CH:25][C:7]2[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22](O)=[O:23])[NH:17]4)=[CH:9][O:10][C:6]=2[CH:5]=1)[CH3:2].[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:32][CH2:33][CH:28]([NH:27][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][C:8]2[C:7]4[CH:25]=[CH:26][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[O:10][CH:9]=2)[CH:21]=[CH:20][CH:19]=3)=[O:23])[CH2:29][CH2:30]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: CCOc1ccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-ethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 30a and amine 14.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][OH:8].[H-].[Na+].Cl[C:15]1[C:20]([N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[N:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[O:5][CH2:6][CH2:7][O:8][C:15]1[C:20]([N:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Reactant: OCCOc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc(O)c2)CC1
Temperature: 65 °C
Reaction time: 1.75 h
Yield: 94 %

Procedure:
To a stirred solution of 2-(3-hydroxyphenoxy)ethanol (7.71 g, 0.05 mol) in dry DMF to (100 mL) at ˜0° C. (ice bath) was added NaH (3.90 g, 0.163 mol) in portions under N2. When the H2-evolution had ceased, a solution of 2-chloro-3-(4-tert-butoxycarbonyl-1-piperazinyl)pyrazine (0.05 mol, 14.9 g; from Example 52, Step 1) in dry DMF (70 mL) was added in one portion. The mixture was stirred at 65° C. for 1.75 h. After cooling, the reaction was quenched by addition of H2O in DMF. The mixture was filtered and concentrated, in vacuo. The residue was dissolved in EtOAc, washed with 1 M KHSO4 and water, dried (Na2SO4+Norit), and concentrated in vacuo to give the title compound as a beige sticky oil. Yield 94%. This product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=O)=[N:19][N:18]=[C:17]2[Cl:33])=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.NN>>[Cl:33][C:17]1[N:16]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:6]=3[C:23]([C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:25]=3)=[N:22][CH2:21][C:20]2=[N:19][N:18]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1-n1c(Cl)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(Cl)n1-2

Procedure:
The 5-chloro-2-(3-chloro-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)benzophenone is reacted with hydrazine to form the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26](O)(=[O:41])[C:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[OH:28].CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:29]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([OH:28])[C:26]([N:16]2[CH2:17][CH2:18][CH2:19][C@H:15]2[C:14]([NH:13][CH2:12][C:11]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=2[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:41])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)C(O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.17 g, 0.45 mmol) in DMF (1 mL) was added benzilic acid (0.23 g, 0.51 mmol), N-methylmorpholine to pH=8 (as measured on wetted E. Merck pH indicator strips), and BOP reagent (0.31 g, 0.70 mmol). After 1 hour of mixing at room temperature, HPLC analysis indicated complete consumption of the starting amine. The mixture was filtered and purified on a preparative HPLC. Pure fractions were pooled and lyophilized to yield 1-(2,2-diphenyl-2-hydroxyethanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide as a solid (0.23 g, HPLC RT=3.75 min, method A; LC-MS m/z=578).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][NH:23][CH2:22][CH2:21]2.C(O)(=O)C.ClC(Cl)C.C([BH3-])#N>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][N:23]([CH2:1][C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:22][CH2:21]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: O=Cc1cc(C(=O)O)c(=O)n2ccccc12
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: O=C(O)c1cc(CN2CCc3cc(Cl)ccc3C2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
In a 2-5 mL Emrys™ process vial, a mixture of the 1-formyl-4-oxo-4H-quinolizine-3-carboxylic acid (76 mg, 0.35 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline (82 mg, 0.49 mmol), glacial acetic acid (0.12 mL, 2.1 mmol) and 1.8 mL of dichloroethane was stirred vigorously. To the stirring mixture was added resin-bound MP-cyanoborohydride (343 mg, 0.70 mmol). The mixture was heated via Emrys Optimizer™ microwave to 120° C. for 30 minutes. Filtration and solvent removal provided material, which was subjected to preparative reverse phase HPLC. Collection of product containing fractions and removal of solvent yielded the title compound that gave a proton NMR spectrum consistent with theory and a high resolution mass spectrum (ES+) m/z of 369.1011 calculated for M+H+ [C20H17Cl1N2O3: 369.1001]: 1H NMR (500 MHz, CD3OD) δ 9.59 (d, J=7.1 Hz, 1H), 8.74 (s, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.18 (t, J=73 Hz, 1H), 7.73 (t, J=6.6 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 4.87 (s, 2H), 4.47 (s, 2H), 3.69 (bs, 2H), 3.20 (t, J=6.0 Hz, 2H).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27](O)=[O:28])[CH:22]=3)[CH:17]=1)[CH2:12]2.[Cl:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][NH:37]2)=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:30][C:31]1[CH:39]=[C:38]2[C:34]([CH2:35][CH2:36][N:37]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:28])=[CH:33][CH:32]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc(Cl)cc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 63 mg (0.37 mmol) 6-chloro-2,3-dihydro-1H-indole, 0.15 mL (0.87 mmol) DIPEA and 130.00 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred for 1 h at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and suction filtered. The precipitate was dried under HV.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.O[Li].O>CO.O>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]([CH2:28][C:29]([OH:31])=[O:30])[CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: COC(=O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Agent: [Li]O
Solvent: CO
Solvent: O
Product: O=C(O)CC1CC2(CCN(C(=O)OC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
2-adamantyl-3-(2-methoxy-2-oxoethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (26 mg, 0.06 mmol) was dissolved in MeOH (1 mL) in an ice-water bath. A solution of LiOH.H2O (4.99 mg, 0.119 mmol) in water (0.2 mL) was added dropwise and the mixture was stirred for 8 h at rt. LC-MS showed that the starting material was consumed completely. The mixture was evaporated to give a residue, which was purified by preparative HPLC to afford 2-(1′-((2-adamantyloxy)carbonyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (12.2 mg, 48%). 1H NMR (400 MHz, CD3OD): δ=0.91 (m, 2H), 1.32 (m, 3H); 1.53-1.71 (m, 6H), 1.75-1.93 (m, 8H), 1.93-2.18 (m, 4H), 2.24 (m, 1H), 2.63 (m, 1H), 2.77 (m, 1H), 2.96-3.24 (br, 2H), 3.62 (m, 1H), 4.10-4.28 (br, 2H), 4.72 (s, 1H), 7.15 (m, 3H), 7.24 (m, 1H).
Reaction SMILES: I.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH2:19][CH:18]3[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH:18]3[CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)CCC1CN(CC(=O)OC(C)(C)C)CCC1N1CCN(c2ccc(C(=N)N)cc2)CC1
Agent: I
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC1CN(CC(=O)O)CCC1N1CCN(c2ccc(C(=N)N)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.45 g of methyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1-(tert-butoxycarbonylmethyl)-3-piperidinepropionate hydroiodide was dissolved in 50 ml of an aqueous solution of 90%-trifluoroacetic acid and stirred at room temperature for 15 minutes. The reaction mixture was concentrated, and the resulting residue was purified by HP-20 column chromatography (using an eluent of water/methanol=10/1) to obtain 0.32 g of 4-[4-(4-amidinophenyl)-1-piperazinyl]-3-methoxycarbonylethyl-1-piperidineacetic acid trifluoroacetate.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:24])[NH:19][CH2:20][CH:21]([CH2:22][NH2:23])[C:11]([C:12]=23)=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:2]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=[O:24])[NH:19][CH2:20][CH:21]([CH2:22][NH:23][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:11]([C:12]=23)=[CH:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: NCC1CNC(=O)c2cccc3c2c1cn3Cc1ccccc1
Agent: Cl
Product: O=C1NCC(CNCc2ccccc2)c2cn(Cc3ccccc3)c3cccc1c23

Procedure:
4 g of oily i-benzyl-3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino(5,4,3-cd]indole (see Example 10 for preparation) were reacted with benzaldehyde by the method described in Example 2, and the resulting Schiff's base was reduced by the method described in Example 2. The reaction mixture was worked up as described in Example 2. 4.3 g of 1-benzyl-3-benzylaminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([CH3:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([CH3:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: Cc1c(F)ccc(C(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(F)ccc(C(=O)N2CCNC(=O)C2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-piperazinone (1 g, 9.99 mmol, commercially available from e.g. Sigma-Aldrich) was then dissolved in dichloromethane (DCM) (40 mL), and to this was added triethylamine (2.78 mL, 19.98 mmol). The solution was cooled to 0° C. before 2-chloro-4-fluoro-3-methylbenzoyl chloride, (2.072 g, 10.99 mmol), from Step 1, in DCM (10 mL) was added dropwise over 1 minute. The solution was then allowed to stir at room temperature for a further 30 minutes before the solvent was evaporated in vacuo. The remaining solid was then re-dissolved in DCM (80 mL) before being washed with water (30 mL), a saturated solution of sodium bicarbonate (30 mL), and brine (30 mL). The solution was then dried over anhydrous sodium sulphate, which was hen removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane at 55° C. for 30 minutes, before being filtered off to yield the product in 2.496 g.
Reaction SMILES: C(O[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[S:14](Cl)(=[O:16])=[O:15])[CH2:10][N:9]([C:18](=O)[C:19](F)(F)F)[CH2:8][CH2:7]2)C.[F-:24].[K+].C(=O)(O)[O-].[Na+]>C(#N)C>[F:24][C:4]1[CH:5]=[CH:6][C:11]([S:14]([C:13]2[C:4]([N:9]([CH3:10])[CH3:8])=[CH:5][C:6]3[CH2:7][CH2:8][N:9]([CH3:10])[CH2:18][CH2:19][C:11]=3[CH:12]=2)(=[O:15])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOc1cc2c(cc1S(=O)(=O)Cl)CN(C(=O)C(F)(F)F)CC2
Reactant: [F-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCc2cc(N(C)C)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Yield: 173.9 %

Procedure:
To a solution of 6-ethoxy-2-(2,2,2-trifluoro-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride (0.34 g, 0.92 mmol) in acetonitrile (3.8 mL) was added potassium fluoride (0.28 g, 4.8 mmol) and 18-crown-16 (1 crystal). The mixture was stirred at room temperature overnight before addition of aqueous sodium bicarbonate to pH 8. The resulting mixture was extracted with ethyl acetate, dried over MgSO4 and evaporated to dryness yielding the subtitled compound as a white solid (0.29 g). MH−354. 1H NMR δ (CDCl3) 1.43-1.53 (3H, t), 2.95-3.07 (2H, m), 3.80-3.93 (2H, m), 4.14-4.26 (2H, m), 4.70-4.80 (2H, d), 6.82-6.90 (1H, d), 7.68-7.75 (1H, d).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CN(C)c1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(CNc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-chloro-3-nitrobenzotrifluoride (5.05 g, 22.4 mmol), 4-(dimethylamino)-benzylamine dihydrochloride (5.0 g, 22.4 mmol), potassium carbonate (9.29 g, 76.2 mmol) and dimethylformamide (60 ml) was stirred at room temperature for 3 days. Water (60 ml) was added and the mixture was stirred for 0.5 h followed by filtration. The crystalline product was triturated with petroleum ether. Yield 6.08 g, 80%. M.p. 158-160° C.
Reaction SMILES: [CH2:1]([NH:8]CCC1C2C(=CC=C(F)C=2OC)N(C)C=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([N:26]1[C:34]2[C:29](=[C:30]([O:36][CH3:37])[CH:31]=[CH:32][C:33]=2[F:35])[C:28]([CH2:38][CH2:39]O)=[CH:27]1)[CH3:25]>>[CH2:1]([NH:8][CH2:39][CH2:38][C:28]1[C:29]2[C:34](=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[O:36][CH3:37])[N:26]([CH2:24][CH3:25])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1cc(CCO)c2c(OC)ccc(F)c21
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Product: CCn1cc(CCNCc2ccccc2)c2c(OC)ccc(F)c21
Yield: 68 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 20-3 was used as starting material, giving compound 20-4 in 68% yield as a white solid, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 9.25 (br, 2H), 7.54-7.57 (m, 2H), 7.42-7.44 (m, 3H), 7.16 (s, 1H), 6.82 (dd, J=12.4, 8.5 Hz, 1H), 6.35 (dd, J=8.5, 2.7 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.17 (s, 2H), 3.75 (s, 3H), 3.12 (br, 4H), 1.32 (t, J=7.1 Hz, 3H). LRMS: calc 326.2 found 327.2 [MH]+.