Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[CH:21][CH:20]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]=1[CH3:17].Cl.[NH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50]>>[F:1][C:2]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:3]=1[CH2:4][N:5]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=2)[O:27][CH2:28][CH2:29][CH2:30][C:31]([NH:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])=[O:32])=[CH:37][CH:38]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:14])=[O:15])[C:7]=1[CH3:17]
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F
Reactant: CCOC(=O)CCCN
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccc(Oc2cccc(OCCCC(=O)NCCCC(=O)O)c2)cc1)Cc1ccc(F)cc1F

Procedure:
The product from Example 120D and ethyl 4-aminobutyrate hydrochloride was processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.96 (s, 1 H), 7.83 (t, 1 H), 6.88-7.32 (m, 11 H), 6.68 (m, 1 H), 6.49 (m, 2 H), 4.08 (s, 2 H), 4.05 (s, 2 H), 3.91 (t, 2 H), 3.03 (dd, 2 H), 2.90 (s, 3 H), 2.33 (s, 3 H), 2.19 (t, 4 H), 2.07 (s, 1 H), 1.89 (m, 2 H), 1.59 (m, 2 H); MS (ESI) m/z 696 (M+H+).
Reaction SMILES: [OH-].[Na+].C(OC([C:8]1([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:12][CH2:11][N:10]([CH3:13])[C:9]1=[O:14])=O)C.Cl>C(O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])=[N:16][CH:17]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cn2)CCN(C)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(c2ccc(Br)cn2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aqueous NaOH solution (1 mol/L, 3 mL) was added to 3-(5-bromo-pyridin-2-yl)-1-methyl-2-oxo-pyrrolidine-3-carboxylic acid ethyl ester (0.50 g) in ethanol (10 mL) at room temperature. The solution was stirred at room temperature overnight and then neutralized with 1 M aqueous hydrochloric acid. The resulting mixture was concentrated and the residue was taken up in ethyl acetate and filtered to remove the non-dissolving parts. The filtrate was dried (MgSO4) and concentrated. The residue was chromatographed on silica gel (ethyl acetate/methanol 9:1) to give the title compound as a colorless oil. Yield: 0.28 g (71% of theory); Mass spectrum (ESI+): m/z=255/257 (Br) [M+H]+.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.C([N-]C(C)C)(C)C.[Li+].C([C:20]([O:22][CH3:23])=[O:21])#N>C1COCC1>[C:20]([CH:4]1[C:3](=[O:9])[CH2:2][CH:1]2[CH2:8][CH:5]1[CH2:6][CH2:7]2)([O:22][CH3:23])=[O:21]
Reactant: O=C1CC2CCC(C1)C2
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1C(=O)CC2CCC1C2
Temperature: -78 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To bicyclo(3.2.1)octan-3-one, 227 (6.42 g, 51.7 mmol) in THF (75 mL), lithium diisopropyl amide (31 mL, 62 mmol) in THF (125 mL) was added dropwise at −78° C. The mixture was stirred at −78° C. for 1 h and methyl cyanoformate (4.9 mL, 62 mmol) was added. The cooling bath was removed and the reaction allowed to warm to room temperature. After stirring for 2 h, saturated aqueous NaCl (32 mL) was added and about half of THF removed on a rotary evaporator. The remaining solvent was extracted with ether (3×150 mL) and the dried (Na2SO4) ether layer concentrated to dryness. The residue was purified by flash chromatography (eluent: 10% EtOAc/hexanes) to afford 7.85 g (83%) of 3 as a colorless oil: Rf0.56 (10% EtOAc/bexanes); 1H-NMR (75:15:10 mixture of 2-en-3-ol, 2-α, and 2-β-carbomethoxy-3-keto tautomers) δ11.87 (s, 1H); 3.73 (s, 3H), 3.70 (s, 0.6H), 3.69 (s, 0.4H), 3.42 (m, 0.2H), 3.19 (m, 0.13H), 2.93 (m, 1H), 2.81 (m, 0.13H), 2.71 (m, 0.2H), 2.65 (ddd, 0.13H), J=18, 4, 2 Hz), 2.55 (ddd, 1.2H, J=18, 4, 2 Hz), 2.41 (m, 1H), 2.34 (m, 0.2H), 2.29 (m, 0.13H), 2.03 (dd, 1H, J=18, 2 Hz), 1.65-1.95 (m, 4.4H), 1.30-1.55 (m, 3.6H). 13C-NMR (only the signals corresponding to the 2-en-3-ol tautomer are reported) δ172.00, 171.19, 105.38, 51.33, 40.19, 35.92, 35.58, 32.91 (2C), 29.90.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CC(C)=O.[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>O>[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:26])([O-:21])=[O:20]
Reactant: Nc1ccccn1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1ccccn1)c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a mixture of 2-aminopyridine (28.2 g), triethylamine (45 ml) and acetone (600 ml), 3-nitrobenzoyl chloride (55.8 g) was gradually added with stirring under ice cooling. The mixture was stirred for 30 minutes under the same condition, then for one hour at room temperature. Thereafter, the reaction solution was poured into 3 liters of water, and the resulting crystal was collected by filtration, washed with water, and recrystallized from methanol to provide 58.5 g of 3-nitro-N-2-pyridylbenzamide as a colorless acicular crystal (yield: 80%, m.p. 156°-157° C.). Hydrogen was bubbled into a mixture of the 3-nitro-N-2-pyridylbenzamide (15.9 g), 10% palladium-carbon (1.5 g) and ethanol (300 ml). After a stoichiometric amount of hydrogen was absorbed, the catalyst was removed, the reaction mixture was concentrated under vacuum, and the residue was recrystallized from ethanol to provide 7.2 g of a colorless acicular crystal of 3-amino-N-2-pyridylbenzamide (yield: 52%, m.p. 113°-115° C.). To a mixture of the 3-amino-N-2-pyridylbenzamide (6.4 g), triethylamine (4.5 ml) and acetone (60 ml), propionic acid chloride (2.8 g) was gradually added with stirring at room temperature. After one hour of stirring, the reaction mixture was poured into 200 ml of water which was then made weakly alkaline by gradually adding a 10% solution of sodium hydroxide. The resulting crystal was collected by filtration, washed with water and recrystallized from methanol to provide 7.0 g of 3-propionyl-N-2-pyridylbenzamide as a colorless acicular crystal (compound 1) (yield: 87%, m.p. 128°-129° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[N:10][CH:9]=[C:8]2Cl)=[O:4].C([O-])=O.[Na+].C(N(CC)C(C)C)(C)C.O>CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[N:10][CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2nncc(Cl)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2nnccc2c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 10.3 %

Procedure:
To a solution of 4-chloro-cinnoline-6-carboxylic acid methyl ester (192 mg, 0.863 mmol) in dimethylsulfoxide (30 mL) were added sodium formate (70 mg, 1.04 mmol), tetrakis(triphenylphosphine)palladium(0) (198 mg, 0.702 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.21 mmol), and the mixture was stirred for 1.5 hours at 90° C. After cooling to room temperature, water was added, ethyl acetate extraction was carried out, the organic layer was washed with water and brine, then, after drying over anhydrous sodium sulfate, the organic layer was evaporated. The resulting solid was washed with diethyl ether, then, purified by silica gel column chromatography (hexane-ethyl acetate), and the title compound (16 mg, 0.089 mmol, 10%) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.ClC1C(C(F)(F)F)=CC=CC=1C(NC(C1(N(C)C)CCCC1)C1C=CC=CC=1)=O.[CH3:46][C:47]1[C:55]([CH3:56])=[CH:54][CH:53]=[CH:52][C:48]=1[C:49](O)=[O:50].O.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:49](=[O:50])[C:48]2[CH:52]=[CH:53][CH:54]=[C:55]([CH3:56])[C:47]=2[CH3:46])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)C1(C(NC(=O)c2cccc(C(F)(F)F)c2Cl)c2ccccc2)CCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC(c2ccccc2)C2(N(C)C)CCCC2)c1C
Reaction time: 20 h
Yield: 86 %

Procedure:
A mixture of {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.102 g, 0.47 mmol), 2,3-dimethylbenzoic acid (0.100 g, 0.67 mmol), 1-hydroxybenzotriazole hydrate (0.092 g, 0.6 mmol) and PS-DCC (0.63 g of 1.3 mmol/g loading, 0.82 mmol) in DCM (7 ml) was shaken for 20 h. The mixture was filtered and the resin washed with DCM (2×4 ml). Combined organics were washed with saturated sodium hydrogen carbonate (20 ml), the layers separated and the organic layer applied to a 2 g SCX cartridge. The cartridge was washed with DCM (2 volumes), 50% methanol in DCM (1 volume) and methanol (2 volumes). Elution with 1M ammonia in methanol (2 volumes) and evaporation of the solvent afforded a colourless gum. Chromatography on silica gel (10 g) eluting with 0-100% ethyl acetate in pentane gradient afforded the title compound as a colourless solid (0.14 g; 86%). 1H NMR (CDCl3) δ: 0.90-1.15 (1H, m), 1.20-1.38 (1H, m), 1.40-1.55 (2H, m), 1.60-1.75 (2H, m), 1.79-1.90 (2H, m), 2.22 (6H, s), 2.28 (6H, s), 5.15 (1H, d, J=6 Hz), 6.98 (1H, d, J=6 Hz), 7.10-7.15 (1H, m), 7.19-7.27 (3H, m), 7.29-7.35 (2H, m), 7.39-7.43 (2H, m). Mass spectrum (Electrospray LC/MS), ES+: Found 351 (MH+). C23H30N2O requires 350. Ret. time 1.90 min. The title product was converted to the corresponding hydrochloride salt (0.150 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[O:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[O:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C:3]([NH:5][C@@H:6]2[CH2:11][O:10][C:9]3=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]3[CH2:7]2)=[O:4])[CH2:25][CH2:24]1
Reactant: Fc1cc(OC2CCNCC2)ccc1OC(F)(F)F
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(OC(F)(F)F)c(F)c2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 54.4 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(3-fluoro-4-(trifluoromethoxy)phenoxy)piperidine (279 mg, 1.0 mmol) as crude materials, 137 mg title compound was generated and yield was 55%.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:37])[CH:6]1[CH2:38][CH3:39])C=C.[Cl:40]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:40][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:37])[CH:6]1[CH2:38][CH3:39]
Reactant: ClCl
Reactant: C=CCSC1C(CC)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccccc1)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccccc2)C(=O)C(C)(C)C)C1Cl
Temperature: 25 °C
Yield: 77.3 %

Procedure:
To a solution of 2.47 g 4-nitrobenzyl 2-(4-allylthio-3-ethylazetidin-2-on-1-yl)-3-phenoxy-3-trimethylacetylthiopropenate in dichloromethane at -20° was added a solution of 8.4 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethane acetate mixtures afforded 1.782 g of the title compound as a pale yellow foam (78% of the theoretical yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:22][C:23]([C:25]2([NH:40]C(=O)OC(C)(C)C)[CH2:30][CH2:29][N:28]([C:31]3[C:32]4[CH:39]=[CH:38][NH:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:27][CH2:26]2)=[O:24])[CH2:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[CH:11][CH:10]=1>ClCCl>[NH2:40][C:25]1([C:23]([NH:22][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[CH2:16][C:17]([N:19]([CH3:20])[CH3:21])=[O:18])=[O:24])[CH2:26][CH2:27][N:28]([C:31]2[C:32]3[CH:39]=[CH:38][NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH2:29][CH2:30]1
Reactant: CN(C)C(=O)CC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
TFA (1.0 mL) was added to a suspension of tert-butyl 4-(1-(4-chlorophenyl)-3-(dimethylamino)-3-oxopropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 98) (770 mg, 0.24 mmol) in dichloromethane (10 mL) under argon. The resulting solution was stirred at room temperature for one night. The solvents were removed in vacuo and the reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-3-(dimethylamino)-3-oxopropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (74.0 mg, 64.8%) as a white powder.
Reaction SMILES: Cl[C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25]([NH2:28])[CH2:26][NH2:27]>CN1C(=O)CCC1>[NH2:27][CH2:26][CH2:25][NH:28][C:2]1[C:14]2[N:13]3[C:8]([C:9]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[CH3:23])=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[N:5]=[C:4]([CH3:24])[CH:3]=1
Reactant: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(Cl)c23)c(C)c1
Reactant: NCCN
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2cccn3c2cc2nc(C)cc(NCCN)c23)c(C)c1

Procedure:
Heat a solution of 4-chloro-2-methyl-9-(2,4,6-trimethylphenyl)pyridino[2,3-b]-indolizine (0.35 g, 1.04 mmol), and ethylene diamine (0.32 g, 1.04 mmol) in dry NMP (3 mL) at 100° C. for 5 h. Pour the cooled mixture onto water (30 mL) and extract twice with EtOAc (30 mL). Wash the combined extract with brine (30 mL), dry, and evaporate in vacuo. Purify by preparative TLC (20% MeOH in CH2Cl2 with 1% ammonium hydroxide) to obtain the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]([C:32]#[N:33])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][CH:20]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.C(N(CC)CC)C.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>ClCCl>[C:26]([O:25][C:24]([N:23]([CH3:31])[CH:20]1[CH2:19][CH2:18][CH:17]([O:16][C:7]2[C:6]3[C:5]4[C@@H:4]([CH2:3][CH:2]([NH:1][C:42](=[O:43])[O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)[C:32]#[N:33])[CH2:15][CH2:14][C:13]=4[S:12][C:11]=3[N:10]=[CH:9][N:8]=2)[CH2:22][CH2:21]1)=[O:30])([CH3:29])([CH3:27])[CH3:28]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)C#N)CC4)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)NC(=O)OCc2ccccc2)CC4)CC1
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(2-amino-2-cyanoethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (800 mg, 1.70 mmol, 1.00 equiv) and triethylamine (340 mg, 3.36 mmol, 2.00 equiv) in dichloromethane (50 mL) was added dropwise a solution of benzyl chloroformate (320 mg, 1.88 mmol, 1.10 equiv) in 10 mL of DCM at 0° C. The resulting solution was stirred for 30 min at this temperature and then quenched with water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5) to give benzyl N-[2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-3-yl]-1-cyano ethyl]carbamate (0.5 g, 49%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].[BH4-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1
Temperature: 0 °C
Yield: 93.8 %

Procedure:
To a mixture of 4-cyanobenzaldehyde (5.00 g) in ethanol (50 mL) and tetrahydrofuran (20 mL) was added sodium borohydride (2.16 g) under ice-water cooling, and the mixture was stirred for an hour at 0° C. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-cyanobenzyl alcohol (4.76 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22](O)=[O:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc2cc(C(=O)O)cc(-c3ccnc(Cl)c3)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2cc(CO)cc(-c3ccnc(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
To a solution of 1-(2-chloro-4-pyridyl)-3-carboxy-6,7-dimethoxynaphthalene (2.3 g) in tetrahydrofuran (60 ml) is added dropwise a solution of sodium aluminum bis(2-methoxyethoxy) hydride (70% toluene solution, 2.36 ml) in tetrahydrofuran at -10° C., and the mixture is stirred at room temperature for one hour. To the mixture is added dropwise a solution of sodium aluminum bis(2-methoxyethoxy) hydride (70% toluene solution, 1.57 ml) in tetrahydrofuran (5 ml), and the mixture is heated with stirring at 40° C. for one hour. To the mixture is added methanol, and thereto is added an aqueous sodium hydroxide solution (sodium hydroxide (1.6 g) in water (20 ml)), and the mixture is stirred at 50° C. for 30 minutes. The reaction residue is extracted with ethyl acetate, and extracted with dichloromethane. The organic layer is washed with water, dried, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=19:1), and crystallized from ether to give 1-(2-chloro-4-pyridyl)-3-hydroxymethyl-6,7-dimethoxynaphthalene (531 mg, yield; 24%).
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([OH:22])=O.[Cl:23][C:24]1[CH:33]=[CH:32][C:27](C(OC)=O)=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:20](=[O:22])[CH2:19][C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
411 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C., under a nitrogen atmosphere, 350 ml of THF are added, followed dropwise by a solution of 67.7 g of 2,4-dichlorophenylacetic acid in 70 ml of THF and the mixture is kept stirred for 2 hours while the temperature is maintained below −40° C. 53.5 g of methyl 4-chlorobenzoate are then added dropwise and at −60° C. and the mixture is kept stirred while the temperature is allowed to rise to 10° C. The reaction mixture is poured over an ice/1 liter 2N HCl mixture, the organic phase is washed with a saturated NaHCO3 solution, with water, extracted with ether, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is taken up in pentane and the crystallized product formed is drained. 70 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(NC(C)C)(C)C.C([Li])CCC.[C:25](O)(=O)[C:26](O)=[O:27]>CCCCCC.C(N=CC)(C)(C)C.ClP(=O)(OCC)OCC.O1CCCC1>[CH2:5]([C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[CH:25][CH:26]=[O:27])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: O=C(O)C(=O)O
Reactant: CCCCCC(=O)CCCCC
Agent: CC=NC(C)(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCC(=CC=O)CCCCC
Reaction time: 72 h

Procedure:
The compound was prepared according to the procedure described in Example 84 except that the reaction was worked up after 3 days. The following reagents were used: 6-undecanone (17 g), diisopropylamine (32.2 mL), 1.6M n-butyl lithium in hexane (143 mL), acetaldehyde N-tert-butylimine (14.75 mL), diethyl chlorophosphonate (16.6 mL) and tetrahydrofuran (200 mL). The work up, varied only in that the oxalic acid catalyzed hydrolysis was run overnight at room temperature, gave the crude aldehyde which was purified by HPLC (ether-hexane; 1:16.6) to yield 15.5 g of 3-pentyl-2-octenal as an oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4S[C:30]([CH:33]5[CH2:38][NH:37][CH2:36][CH2:35][NH:34]5)=[CH:31][CH:32]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].Br[C:43]1SC(C2CNCCN2)=C[CH:44]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:32]=[CH:31][C:30]([CH:33]5[CH2:38][NH:37][CH2:36][CH2:35][NH:34]5)=[CH:44][CH:43]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C5CNCCN5)s4)cc23)CC1
Reactant: Brc1ccc(C2CNCCN2)s1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C5CNCCN5)cc4)cc23)CC1
Yield: 25.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperazinyl)-2-thienyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2-(4-bromophenyl)piperazine (94 mg, 0.39 mmol) for 2-(5-bromo-2-thienyl)piperazine to afford 20.5 mg of the title compound (25.9%).