Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH:19]([CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:20])[CH:3]=1.[ClH:28].[N:29]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30]1>>[ClH:28].[CH3:27][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:19]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:11]2[C:10]3[CH:12]([CH3:16])[CH2:13][CH2:14][CH2:15][C:9]=3[C:8]([CH3:17])([CH3:18])[O:7][C:6]=2[CH:5]=1)[CH3:20]
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CCC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CCC1

Procedure:
1-Hydroxy-3-(3-methyl-2-octyl)-7,8,9,10-tetrahydro-6,6,10-trimethyl-6H-dibenzo[ b,d] pyran from Example 32 is reacted with γ-pyrrolidinobutyric acid hydrochloride following the procedure of Example 9 to produce 3-(3-methyl-2-octyl)-1-[4-(pyrrolidino)-butyryloxy]-7,8,9,10-tetrahydro-6,6,10-trimethyl-6H-dibenzo[ b,d] pyran hydrochloride.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C:24]2([CH2:28][CH:27]([C:29]([NH2:31])=[O:30])[NH:26][CH2:25]2)[CH2:23]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH:27]([C:29]([NH2:31])=[O:30])[CH2:28][C:24]4([CH2:22][CH2:23]4)[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)C1CC2(CC2)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: NC(=O)C1CC2(CC2)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Yield: 37.1 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 18.6 mg, 106 μmol) was reacted with 5-azaspiro[2.4]heptane-6-carboxamide hydrochloride (Example 135 b, 18.6 mg, 106 μmol) to obtain the title compound (16 mg, 56%) as colorless liquid, MS (EI): m/e=407.3 [MH+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]3[C:19](=O)[NH:20][CH2:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([CH2:13][O:14][C:15]2[CH:26]=[CH:25][C:18]3[CH2:19][NH:20][CH2:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1NCCOc2cc(OCc3ccccc3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(COc2ccc3c(c2)OCCNC3)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
1M Lithium aluminium hydride (62.4 ml, 62.4 mmol) in THF was added under argon to a stirred solution of 8-[(phenylmethyl)oxy]-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (Preparation 27) (8.39 g, 31.2 mmol) in THF (150 ml) with ice bath cooling over 5 minutes. The resulting solution was heated with stirring at 60° C. for 3 hours. The reaction was cooled and carefully quenched by slow addition with ice cooling of 150 ml of 2M sodium hydroxide followed by 150 ml of EtOAc. The organics were separated and aqueous extracted with 100 ml of EtOAc. The combined organic extracts were dried (magnesium sulphate) and evaporated to give the title compound (7.53 g) as a light coloured oil. MS (ES) C16H17NO2 requires 255; found 256 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH2:14][CH:15]=O)[C:7]=2[N:8]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl.C(Cl)(Cl)Cl.C(O)(=O)C>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]4[C:7]5[N:8]=[C:3]([O:2][CH3:1])[N:4]=[CH:5][C:6]=5[CH:12]=[CH:11][C:10]4=[O:13])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1ncc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COc1ncc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a solution of 0.33 g of (2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)acetaldehyde in 15 mL of dichloromethane, a solution of 0.53 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 5.3 mL of dichloromethane, and 87 μL of acetic acid were added, and the mixture was stirred at room temperature for 1 hour 30 minutes. To the reaction mixture, 0.40 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 2 hours 30 minutes. After leaving overnight, the mixture was stirred at room temperature for 4 hours. Chloroform and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using gradient elution with chloroform:methanol=50:1 to 10:1 to obtain 0.55 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(2-methoxy-7-oxopyrido(2,3-d)pyrimidin-8(7H)-yl)ethyl)piperidin-4-yl)carbamate as a light yellow foam.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[C:10]([OH:14])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3]1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5][C:4]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(O)cc2S(=O)(=O)C1
Reactant: CCOC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Yield: 93 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (synthesised by the of WO9616051 for the corresponding 3-butyl-3-ethyl analogue; 2.0 g, 4.16 mmol), ethyl bromoacetate (0.84 g, 5.03 mmol), sodium carbonate (2.0 g, 18.9 mmol) and tetrabutylammonium bromide (80 mg, 0.25 mmol) were added to MeCN (20 ml). The mixture was refluxed for 2 hours and then evaporated under reduced pressure. The residue was extracted with DCM/water. The DCM layer was separated and evaporated under reduced pressure. The residue was purified by column chromatography. The product was eluted with DCM/EtOAc (90:10) to give the title compound 2.2 g (93%). NMR 0.7–0.8 (m, 6H), 1.0–1.6 (m, 15H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0–7.3 (m, 6H), 7.4 (s, 1H).
Reaction SMILES: CC[N:3](C1C=CC=CC=1)CC.[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18]([OH:20])=O.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C1COCC1>[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[C:18]([NH2:3])=[O:20]
Reactant: CCN(CC)c1ccccc1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cnccn1
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 425.5 %

Procedure:
Diethylaniline (0.33 μL, 2.1 μmol, 1.1 equiv) was added in one portion to a stirred solution of the amine (1.0 mg, 1.9 μmol, 1 equiv) in THF (0.2 mL) at 0° C. under an argon atmosphere and the solution was stirred for 5 min. 2-Pyrazinecarboxylic acid (0.31 mg, 2.5 μmol, 1.3 equiv), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.48 mg, 2.5 μmol, 1.3 equiv) and 1-hydroxybenzotriazole (0.31 mg, 2.3 μmol, 1.2 equiv) were then added separately, each in one portion, to the above solution at 0° C. The reaction mixture was warmed to 23° C. over 17 h 40 min, then was quenched with saturated aqueous ammonium chloride solution (3 mL). The mixture was diluted with ethyl acetate (10 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layer was dried over sodium sulfate. Concentration in vacuo left a white solid, which was purified by flash column chromatography (80% ethyl acetate-hexanes) to give the pyrazine-2-carboxylic acid amide derivative (1.1 mg, 92%) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:11]1[C:10](=[O:13])[NH:9][C:8](=[O:14])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12]1)(=[O:17])[CH3:16]
Reactant: O=c1[nH]nc(-c2ccccc2)c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1nc(-c2ccccc2)c(=O)[nH]c1=O
Reaction time: 8 h
Yield: 64.3 %

Procedure:
6-phenyl-1,2,4-triazine-3,5(2H,4H)-dione (prepared as described in BMCL, 2005, 43, 4363, 56 mg, 0.296 mmol) was heated in acetic anhydride (2 ml, 21.20 mmol) at 110° C. for 2 h, than was left at r.t. overnight. Solvent was evaporated under reduced pressure, obtaining 44 mg of title compound (64.3% yield).
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH2:11][CH2:12][CH2:13][O:14]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:21]([O:20][C:18]([NH:17][C@@:10]12[CH2:9][NH:8][CH2:16][C@H:15]1[O:14][CH2:13][CH2:12][CH2:11]2)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@]12CCCO[C@@H]1CN(Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CCCO[C@@H]1CNC2
Yield: 122.2 %

Procedure:
A 10% palladium-carbon catalyst (50% wet, 50 mg) was added to a solution of (1R*,6S*)-8-benzyl-6-(tert-butoxycarbonylamino)-2-oxa-8-azabicyclo[4.3.0]nonane (50 mg, 0.152 mmol) in methanol (10 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for 1.5 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure to give 45 mg of (1R*,6S*)-6-(tert-butoxycarbonylamino)-2-oxa-8-azabicyclo[4.3.0]nonane.
Reaction SMILES: [CH3:1][P:2](=[O:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.O>[CH2:8]([N:15]1[CH2:6][CH2:5][P:2](=[O:7])([CH3:1])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: C=CP(C)(=O)C=C
Solvent: O
Solvent: C1CCOC1
Product: CP1(=O)CCN(Cc2ccccc2)CC1
Yield: 70.3 %

Procedure:
A solution of methyl divinyl phosphine oxide (1.16 g, 10.0 mmol) and benzylamine (1.20 mL, 11.0 mmol) in 1:1 THF/water (25 mL) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol: dichloromethane) to afford 1-benzyl-4-methyl-[1,4]azaphosphinane-4-oxide as a white solid (1.57 g, 70% yield).
Reaction SMILES: C(O[C:4]1[CH2:8][CH:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]=1)C.CO[CH:21](OC)[CH2:22][NH2:23].C(O)(=O)C.[OH-].[Na+]>CO.O.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][S:9][CH:7]2[CH2:6][N:5]3[CH:21]=[CH:22][N:23]=[C:4]3[CH2:8]2)=[CH:16][CH:15]=1
Reactant: COC(CN)OC
Reactant: CCOC1=NCC(SCc2ccc(OC)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CSC2Cc3nccn3C2)cc1

Procedure:
2-Ethoxy-4-p-methoxybenzylthio-1-pyroline (930mg) and aminoacetaldehyde dimethylacetal (552mg) were dissolved in 50 ml of methanol and refluxed under heating for one hour after the addition of acetic acid (315mg). Ethyl acetate and water were added thereto after cooling and the solution was made alkaline with 1N sodium hydroxide aq. solution before ,subjecting to distribution therebetween. The ethyl acetate phase was washed with water and saturated aqueous solution of NaCl, then the, phase was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in 70 ml of benzene, p-toluenesulfonic acid monohydrate (1 g) was added and refluxed under heating for three hours. The solvent was distilled off in vacuo, then water and ethyl acetate were added to the residue and the solvent was made alkaline with 5% aqueous solution of sodium bicarbonate before carrying out the distribution. After the ethyl acetate phase was washed with water and dried over Na2SO4, the phase was concentrated in vacuo. The residue was purified by column chromatography using a column packed with 25 g of silica gel [eluent: chloroform/methanol (19:1 v/v)] and the fractions containing the objective compound were combined and concentrated in vacuo so that the objective compound, as brown oil, was obtained (yield: 731mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.CCN(CC)CC.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23])[CH:10]=1
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC(=O)C(C)(C)C)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.15 g, 0.74 mmol) in THF (10 ml) was added NEt3 (0.210 ml, 1.49 mmol) under an atmosphere of nitrogen at ice bath temperature, followed by trimethyl acetyl chloride (XLV) (0.819 mmol) at the same temperature. The reaction mixture was stirred for 1 hour at 0° C., then it was brought to room temperature and stirred for another hour. After completion of the reaction, the solvent was removed under reduced pressure. The crude reaction product was taken in ethyl acetate (50 ml) and washed with water (2×20 ml). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness at reduced pressure to give crude product which was further purified by column chromatography over silica gel (20% ethylacetate/hexane) to yield N-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-2,2-dimethyl-propionamide. Yield: 106 mg, 50%.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:44])([CH3:43])[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:43])([CH3:44])[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41])[NH:13]1)=[O:11]
Reactant: CC(=O)NCCC(C)(C)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)NCCC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 88.8 %

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 122a (60 mg, 0.09 mmol) was reacted with aqueous HCl solution (1 N, 1 mL, 1 mol) in tetrahydrofuran (5 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-5-(4-acetylamino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (50 mg, 89%).
Reaction SMILES: [CH3:1][C@H:2]1[C:10]2[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][C@H:2]1[C:10]2[C:9]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C[C@@H]1CCc2ncnc(C3=CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1CCc2ncnc(C3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
5% Pd/C (40 mg) was added to a solution of (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate (63 mg, 0.20 mmol) in EtOAc (4 mL). The mixture was stirred at room temperature under a hydrogen atmosphere overnight. The mixture was filtered through celite and concentrated to give (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidine-1-carboxylate as an oil (58 mg, 91%), which was used further without purification.
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.[CH2:14]([O:16][C:17](=O)[O:18]CC)[CH3:15]>C1(C)C=CC=CC=1>[CH2:14]([O:16][C:17]([CH:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13])=[O:18])[CH3:15]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCc2ccccc2C1=O
Yield: 64 %

Procedure:
To a stirred suspension of NaH (11 g, 274 mmol, 60% in oil) in toluene was added dropwise 1-tetralone (20 g, 137 mmol) in toluene (50 mL). After the complete addition, the mixture was heated at reflux for 1 h. Then at 60° C. diethylcarbonate was added (24 g, 137 mmol) dropwise and the mixture was again heated at reflux for 2 h. The reaction was quenched with aqueous HCl (4N, 100 mL) and dilute with H2O. Ether (200 mL) was added for the extraction, the organics were dried and concentrated to oil. Distillation (100° C. at 0.1 mm Hg) gave the title compound (19.1 g, 64%). 1H NMR (CDCl3, 200 MHz): δ 1.34 (t, 3H, J 7.0 Hz), 1.38 (t, 3H, J 7.0 Hz), 2.20-3.10 (m, 4H), 3.59 (1H, dd, J 7.0 Hz J 10.0 Hz), 4.24 (1H, q, J 7.0 Hz), 4.28 (q, 1H, J 7.0 Hz), 7.29 (m, 3H), 7.78 (m, 1H), 8.01 (m, 1H), 12.5 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ 14.1, 14.2, 20.5, 26.36, 27.5, 27.7, 54.5. 60.4; 61.1; 96.9. 124.2, 126.5, 126.7, 127.2, 127.6; 128.7, 130.0, 130.4. 131.8. 133.7, 139.3, 143.6. 165.0, 170.1, 172.6, 193.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>>[I:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=3[C:5]#[N:6])[CH2:14][CH2:15]2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccc(I)cc2)CC1
Yield: 84 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 4-iodobenzoyl chloride (187 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-1% methanol/DCM gradient to afford 2-[1-(4-iodo-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a white solid. (273 mg; 84% yield).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[NH:33][C:34]([SH:37])=[N:35][N:36]=2)[CH:27]=1>>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:37][C:34]3[NH:33][C:32]([C:28]4[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[N:36][N:35]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Sc1nnc(-c2cccnc2)[nH]1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(-c4cccnc4)[nH]3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3 H)-dione and 5-(3-pyridinyl)-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[Bi](Cl)(Cl)Cl.[BH4-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH:10]([CH3:12])[CH3:11])=[CH:23][CH:24]=1
Reactant: CC(C)N(Cc1ccc([N+](=O)[O-])cc1)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl[Bi](Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(Cc1ccc(N)cc1)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of the product from Example 24A (42.8 mg, 0.130 mmol) in ethanol (1.3 mL) under a N2 atmosphere was added bismuth trichloride (0.026 mL, 0.39 mmol). The mixture was cooled in a cold-water bath, and sodium borohydride (79 mg, 2.079 mmol) was slowly added portion-wise over several minutes. When the addition was complete, the resulting mixture was stirred at rt for 1 hour, and then filtered through celite and rinsed with methanol. The filtrate was concentrated to ˜½ volume, diluted with 1:3 isopropyl alcohol:CH2Cl2, and washed with saturated aqueous NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (31.9 mg). MS (APCI) m/s 270.5 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][CH:15]=[CH:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH3:4].CN(CCN(C)C)C.[CH2:27]([Li])[CH2:28][CH2:29][CH3:30]>C1COCC1>[CH2:1]([C:5]1([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: CCCCc1c2ccccc2nc2ccccc12
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CCCCC1(CCCC)c2ccccc2Nc2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To an ice-cooled solution of 9-butylacridine (27.0 g, 0.115 mol) and TMEDA (4.1 mL, 0.027 mol) in THF (135 mL), was added 2.5 M n-butyllithium in hexanes (140 mL, 0.350 mol) dropwise. The mixture was stirred at 0° C. overnight and quenched with water. After stirring for an additional 0.5 hours, the reaction mixture was poured into crushed ice and extracted with ethyl acetate. The organic solution was washed with water and dried over MgSO4. The solvent was evaporated and the resulting residue was chromatographed on silica gel (hexanes:ethyl acetate=10:1 as eluent) to give 14.5 g (43%) of yellow powder.