Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[C@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([F:25])[CH:17]=2)[CH2:11]S[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[O:28][S:29]([O-:31])=O.[K+].CC([O-])=O.[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:26])[NH:7][C@@H:8]1[C@@H:13]([OH:14])[C@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([F:25])[CH:17]=2)[CH2:11][S:29](=[O:31])(=[O:28])[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)OC(=O)N[C@H]1CSC[C@@H](Cc2ccc([N+](=O)[O-])c(F)c2)[C@H]1O
Agent: CC(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CS(=O)(=O)C[C@@H](Cc2ccc([N+](=O)[O-])c(F)c2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [(3R*,4R*,5S*)-5-(3-fluoro-4-nitro-benzyl)-4-hydroxy-tetrahydro-thiopyran-3-yl]-carbamic acid tert-butyl ester (0.78 g, 2.0 mmol) in THF (15 mL) was added water (15 mL) and oxone (2.62 g, 4.2 mmol) and the reaction mixture was stirred for 2 h at 25° C. The excess oxone was destroyed after addition of 2 equivalents of NaOAc with sodium meta-bisulfite and the product was extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4 and evaporated. The title compound was obtained as a light yellow solid suitable for use in the next step: TLC (toluene-EtOAc 1:1) Rf=0.18; HPLC RtA=1.67 min; ESIMS [M+NH4]+=436; 1H NMR (600 MHz, DMSO-d6): δ 8.11 (t, 1H), 7.41 (d, 1H), 7.27 (d, 1H), 6.71 (d, 1H), 5.22 (d, 1H), 3.72 (m, 1H), 3.0-3.2 (m, 5H), 2.82 (s, 1H), 2.71 (dd, 1H), 2.17 (dd, 1H), 1.38 (s, 9H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]([OH:25])[CH3:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH:23]([OH:25])[CH3:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: CC(O)c1ccncc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(O)c1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 3.9 %

Procedure:
Using the same reaction conditions as described in example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 150 mg, 0.6849 mmol) was reacted with 1-(3-bromo-pyridin-4-yl)-ethanol (137.6 mg, 0.6849 mmol), 1,4-dioxane (5 mL), copper iodide (13.04 mg, 0.06849 mmol), trans-1,2-diamino cyclohexane (23.52 mg, 0.205 mmol) and potassium phosphate (435.1 mg, 2.05 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 9 mg of the product (3.9% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[CH:19]=O)([O-:3])=[O:2].[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([NH2:35])[C:31]([NH2:34])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1.S(=O)(O)[O-].[Na+]>C1COCC1.Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[C:7]2[C:19]1[NH:35][C:30]2[CH:29]=[C:28]([CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)[CH:33]=[CH:32][C:31]=2[N:34]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(CN2CCOCC2)cc1N
Reactant: O=Cc1nn(C2CCCCO2)c2ccc([N+](=O)[O-])cc12
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1nc3ccc(CN4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 50 %

Procedure:
5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (85 mg, 0.309 mmol) and 4-(morpholinomethyl)benzene-1,2-diamine (64 mg, 0.309 mmol) were dissolved in dry THF (8 mL) and 2N HCl (1 drop) was added. The solution was heated at a gentle reflux for 30 min and then 1N sodium bisulfite (1 mL) was added. After overnight at reflux, the solution was cooled to room temperature, and diluted with ethyl acetate (40 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated. Purification by flash chromatography (20% ethyl acetate/hexane) afforded the title compound as a pale yellow solid in a 50% yield. 1H NMR: (400 MHz, CD3OD): δ 9.42 (d, 1H, J=2.0 Hz), 8.32 (dd, 1H, J=2.0 and 8.8 Hz), 7.92-7.87 (m, 1H), 7.67 (m, 2H), 7.32 (d, 1H, J=8.4 Hz), 5.97 (dd, 1H, J=2.8 and 8.8 Hz), 3.99 (m, 1H), 3.88-3.82 (m, 1H), 3.72 (m, 6H), 2.57 (m, 5H), 2.19 (m, 2H), 1.88 (m, 1H), 1.73 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18](O)=[O:19])[N:9]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:19])[N:9]=1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2Cl)n1
Reactant: C1CCNCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1cc2ccccc2c(-c2ccccc2Cl)n1)N1CCCCC1
Yield: 68.3 %

Procedure:
Operations are carried out as for Example 7, starting with 1.42 g of 1-(2-chlorophenyl) isoquinoline 3-carboxylic acid, 0.58 g of triethylamine, 0.62 g of ethyl chloroformate and 0.55 g of piperidine in 50 ml of chloroform. 1.2 g of 1-[[1-(2-chlorophenyl) 3-isoquinolyl]carbonyl]piperidine, melting at 161° C. is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[CH2:9]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[C:19]([N:27]2[CH2:32][CH2:31][N:30]([C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:29][CH2:28]2)=[C:18]([C:33]#[N:34])[C:17]1=[O:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccco1
Reactant: N#Cc1c(N2CCNCC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Solvent: c1ccncc1
Product: N#Cc1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(Cl)ccc2n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 71 (379 mg, 1 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 361 mg (76%) of white solids. M.P. 221° C. 1H NMR (DMSO-d6): δ 3.70 (m, 4H), 3.97 (m, 4H), 5.48 (s, 2H), 6.67 (dd, J=2.0, 3.6 Hz, 1H), 7.10 (d, J=3.6 Hz, 1H), 7.20 (m, 2H), 7.25 (m, 1H), 7.27 (m, 2H), 7.42 (d, J=9.2 Hz, 1H), 7.70 (dd, J=2.4, 9.2 Hz), 7.90 (s, 1H). EIMS m/z 496 (M+23). Anal. (C26H21ClN4O3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][S:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[NH:11]2)=[CH:4][C:3]=1[O:26][CH3:27].Br[CH:29](Br)[CH3:30].C(N(CC)CC)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][CH2:29][N:11]3[CH:10]([CH2:15][S:14][CH2:13][CH:12]3[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH2:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc(NCC2CSCC(c3ccc(OC)c(OC)c3)N2)ccc1Cl
Reactant: CC(Br)Br
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CCN3C(CSCC3c3ccc(OC)c(OC)c3)C2)ccc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A solution of (4-chloro-3-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-thiomorpholin-3-ylmethyl]-amine (100 mg, 0.245 mmol, 1.0 equivalents), dibromoethane (0.31 ml, 3.55 mmol, 14.5 equivalents) and triethylamine (0.15 ml, 1.09 mmol, 4.5 equivalents) in dimethylacetamide (2 ml) was heated at 90° C. for 4 hours. Additional dibromoethane (0.16 ml, 1.84 mmol, 7.5 equivalents) and triethylamine (0.25 ml, 1.76 mmol, 7.2 equivalents) was added and reaction was stirred for 4 hours at 90° C. Additional dibromoethane (0.14 ml, 1.62 mmol, 6.6 equivalents) and triethylamine (0.10 ml, 0.71 mmol, 2.9 equivalents) were added and reaction was stirred 18 hours at 90° C. Reaction was cooled and filtered to remove triethylammonium hydrobromide. Filtrate was concentrated. Residue was purified on a 1000 micron preparative TLC. 34 mg of 8-(4-chloro-3-methoxy-phenyl)-4-(3,4-dimethoxy-phenyl)-octahydro-pyrazino[2,1-c][1,4]thiazine (Compound 8) was obtained, along with 36 mg recovered starting material. Yield of product: 32%. H1 NMR (400 MHz, CDCl3): 7.19 (1H, d), 6.86 (3H, m), 6.42 (2H, m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.50 (1H, m), 3.19 (2H, dd), 2.92 (1H, m), 2.75 (5H, m), 2.48 (2H, t), 2.15 (1H, dt). MS LC-MS): Calculated for C22H27ClN2O3S 435.14, 435.24.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24]CC)=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>CCO.C1COCC1.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[N:10][N:11]=[C:12]3[C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([OH:24])=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinate (0.120 g, 0.260 mmol) in EtOH (6 mL) and THF (6 mL) was added LiOH (0.0620 g, 2.60 mmol) in water (3 mL) at room temperature. The reaction mixture was stirred at the same temperature for 16 h. Then the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water (5 mL). The reaction mixture was extracted with EtOAc and the aqueous layer was separated. The aqueous layer was acidified to pH 5 with citric acid and extracted with EtOAc. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by HPLC (Condition 13 as described in general methods) to afford 5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)nicotinic acid (0.0150 g, 13.3%). LCMS (Condition 2): retention time 1.54 min, [M-1]=432.0. HPLC (Condition 25): retention time=5.86 min, purity 95.51%. 1H NMR (400 MHz, DMSO-d6) δ 4.66 (d, J=4.4 Hz, 2 H), 6.25 (dd, J=4.0 Hz, J=4.4 Hz, 1 H), 7.20-7.24 (m, 1 H), 7.28 (d, J=7.6 Hz, 1 H), 7.52-7.59 (m, 5 H), 7.68-7.73 (m, 2 H), 7.82 (dd, J=1.2 Hz, J=8.4 Hz, 1 H), 7.91 (dd, J=7.2 Hz, J=8.4 Hz, 1 H), 8.22-8.25 (m, 1 H), 8.35 (dd, J=1.6 Hz, J=2.0 Hz, 1 H), 8.74 (d, J=2.0 Hz, 1 H), 9.09 (d, J=1.6 Hz, 1 H).
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC.O1CCCC1>CCCCCC>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 2,3,4,5,6,7-hexahydroazepine (2.8 ml), a 1.6M solution of butyllithium in hexane (15 ml), and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 2,3,4,5,6,7-hexahydro-1-[(2-phenylquinazolin-4-yl)-carbonyl]-azepine (2 g), melting at 140° C., is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](O)=[O:25])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24](=[O:25])[CH2:2][C:1](=[O:3])[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: CC(=O)c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)CC(=O)c2ccncc2)CC1

Procedure:
Condensation of 4-acetylpyridine with 4-carboxymethylpiperidine-1-carboxylic acid tert-butyl ester, utilising the protocol described in Preparation 22, afforded the title compound: m/z (ES+)=247.2 [M-Boc+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH:14]=O)[C:7]=2[CH:16]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[N:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]3)[C:7]=2[CH:16]=1
Reactant: COc1ccc2nnc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2nnc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Yield: 34 %

Procedure:
A mixture of [6-(methyloxy)-3-oxo-1,2,4-benzotriazin-4(3H)-yl]acetaldehyde (as the methyl hemiacetal) (89 mg, 0.346 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (69 mg, 0.346 mmol) in chloroform (5 ml) and MeOH (0.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (220 mg, 1.038 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (20 ml). The reaction was then extracted with 20% MeOH in DCM (3×100 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-5% MeOH/DCM gradient to provide the desired compound (48 mg, 34%).
Reaction SMILES: Br.Cl[C:3]1[C:4]2[CH2:15][CH2:14][CH2:13][C:5]=2[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[O-:16][CH2:17][CH3:18].[Na+]>C(O)C>[CH2:17]([O:16][C:3]1[C:4]2[CH2:15][CH2:14][CH2:13][C:5]=2[C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1)[CH3:18]
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCC3
Reactant: CC[O-]
Agent: Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c2c1CCC2

Procedure:
6-Chloro-8,9-dihydro-7H-cyclopenta[d][1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.017, 1.0 g) was dissolved in ethanol (50 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (1.41 g) and stirred at 60° C. for 1 h. After the solvent had been drawn off, the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 60 min). The clean product fractions were combined and dried. 662 mg of the title compound were obtained.
Reaction SMILES: [H-].[Na+].NC[CH2:5][N:6]1[C:14](C2C=CC=C(Cl)C=2)=[C:13]2[C:8]([N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH3:23])[C:12]2=[O:22])=[CH:7]1.[CH3:26][Si:27]([CH2:30][CH2:31][O:32]CCl)([CH3:29])[CH3:28]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1COCC1>[CH3:25][N:9]1[C:8]2=[CH:7][N:6]([CH2:5][O:32][CH2:31][CH2:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:14]=[C:13]2[C:12](=[O:22])[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1c(=O)c2cn(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Sodium hydride (60% in mineral oil, 335 mg, 8.4 mmol) was added to an ice cooled partial suspension of 1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (Intermediate B step 1) (1.00 g, 5.6 mmol), SEM-Cl (1.485 mL, 8.4 mmol) and benzyl triethylammonium chloride (76 mg, 0.34 mmol) in THF (15 mL). The mixture was allowed to reach room temperature slowly and was stirred for 18 hours. The reaction mixture was quenched cautiously with sat ammonium chloride solution (80 mL, added dropwise), then was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with water (1×40 mL), brine (1×40 mL) then dried with magnesium sulfate and the solvent was removed under vacuum. The residue was triturated with iso-hexane and dried under vacuum at 50° C. to afford the title compound.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[NH:8][C:7](=O)[CH2:6][O:5][CH2:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[F:1][CH:2]([F:17])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[NH:8][C:7](=[S:27])[CH2:6][O:5][CH2:4]1
Reactant: O=C1COCC(c2ccccc2F)(C(F)F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Fc1ccccc1C1(C(F)F)COCC(=S)N1
Temperature: 68 °C
Yield: 195 %

Procedure:
A mixture of 5-difluoromethyl-5-(2-fluoro-phenyl)-morpholin-3-one (141 g, 575 mmol) and Lawesson's reagent (132 g, 316 mmol) in 1400 ml of THF was heated at 68° C. for 1 h, cooled down and then evaporated. The residue was dissolved in 1 L DCM and filtered over 2 Kg silica gel with 10 L DCM to give 161 g of the title compound in the form of a greenish resin that slowly crystallized. The compound was used without further purification.
Reaction SMILES: [CH:1]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[CH:1]1([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCCCCCCCCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1CCCCCCCCCCCCCC1

Procedure:
To a solution of alcohol 52 (300 mg, 1.25 mmol) in CH2Cl2 (20 mL) was added PCC (404 mg, 1.87 mmol) at room temperature. The reaction was monitored by TLC (50% hexanes/50% CH2Cl2) until complete (60 min) Upon reaching completion, the mixture was then diluted with Et2O, filtered through Celite and concentrated in vacuo to give aldehyde 53 as a yellow oil that was used without further purification (250 mg crude). 1H NMR (CDCl3) δ 9.61 (s, 1H), 2.43 (m, 2H), 2.29 (m, 1H), 1.62 (m, 4H), 1.49 (m, 4H), 1.44-1.31 (m, 20H). This aldehyde was found to be unstable and was best used immediately in subsequent steps.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[N+:18]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(OCC)(=O)C.[Pd]>[NH2:18][C:9]1[CH:10]=[C:11]([S:14]([NH2:17])(=[O:15])=[O:16])[CH:12]=[CH:13][C:8]=1[NH:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(S(N)(=O)=O)ccc1NC1CCCCC1
Yield: 106.4 %

Procedure:
A solution of intermediate 66 (2.56 g, 8.55 mmol) in a mixture of methanol (50 mL) and ethyl acetate (50 mL) was hydrogenated over 10% palladium on carbon (0.14 g) at 50 psi for 2.5 h. The reaction mixture was filtered and concentrated to afford the product as a crude purple-brown foam (2.45 g, 100%). ESI-MS m/e 270.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:38])([F:37])[F:36])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.[Li+].[OH-]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([OH:32])=[O:31])[CH2:24][CH2:23]4)[C:12]([C:35]([F:37])([F:38])[F:36])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(-c4ccc(OC)cc4)ccc3C(F)(F)F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ccc(C(F)(F)F)c(NCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[6-(4-methoxyphenyl)-3-(trifluoromethyl)-2-pyridinyl]amino}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 307) (0.05 g, 0.09 mmol) in THF (1 mL), methanol (1 mL), and water (0.5 mL) was added LiOH (0.02 g, 0.85 mmol). The mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified to pH ˜5 using H3PO4 (5% aqueous solution). The aqueous solution was then extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered, and then concentrated under reduced pressure to give the product (0.034 g, 80%). 1H NMR (400 MHz, CD2Cl2) δ 8.03 (d, 2H), 7.68 (d, 1H), 7.07 (dd, 2H), 6.97 (d, 2H), 6.80 (s, 1H), 6.72 (dd, 1H), 5.37 (b, 1H), 4.11 (t, 2H), 3.91-3.81 (m, 5H), 3.56-3.48 (m, 1H), 2.95-2.77 (m, 3H), 2.15-2.37 (m, 2H), 2.23-2.18 (m, 2H), 1.65-1.55 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:26](Cl)(=[O:28])[CH3:27].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:26]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[CH:24][CH:25]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Yield: 79.2 %

Procedure:
1-[1-(4-Aminomethylphenethyl)piperidin-4-yl]indoline (0.6 g) was dissolved in tetrahydrofuran (9.0 ml). Under ice cooling, acetyl chloride (0.14 ml) was added dropwise thereinto and the resultant mixture was stirred for 2 hr. After adding a saturated aqueous solution of sodium bicarbonate, the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.518 g) as a pale yellow oil (yield: 79.2%).
Reaction SMILES: [C-]#N.[K+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>O>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:21])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Yield: 41.5 %

Procedure:
To a solution of KCN (5 g) in water (35 mL) is added 4-methoxybenzaldehyde (27.2 g, 0.2 mole), benzaldehyde (21.2 g, 0.2 mole) and 95% ethanol (70 mL). The mixture is refluxed under nitrogen for 4.5 hours and the ethanol removed in vacuo. Water (200 mL) is added to the residue and then distilled off at reduced pressure (to remove remaining unreacted bezaldehyde). The procedure is repeated twice and the residual water azeotroped with ethanol. The crude product (56.3 g, orange semi-solid) is purified by flashchromatography (on silica Merck-60, preabsorbed in dichloromethane-ethyl acetate and eluted with hexane-ethyl acetate 8:2) to yield a light yellow solid (20.1 g, 41.5%), m.p. 99°-101° C.