Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([OH:35])([C:12]3[S:13][C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([NH:24][C:25]5[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[N:18]=4)=[CH:15][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([O:38]C)=[O:37].[OH-].[K+]>C1COCC1.CO>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([OH:35])([C:12]3[S:13][C:14]([C:17]4[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([NH:24][C:25]5[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:27][N:26]=5)[N:18]=4)=[CH:15][N:16]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:36]([OH:38])=[O:37]
Reactant: COC(=O)c1ccc2c(c1Br)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C3(O)CCCc4c3ccc(C(=O)O)c4Br)s2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of methyl 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylate (50 mg, 0.081 mmol) in THF (1.6 mL) was added aqueous potassium hydroxide (172 μl, 1.61 mmol), and the mixture was stirred for 16 h at rt, after which time the reaction mixture was diluted with MeOH (2 mL), filtered, and purified by reverse phase HPLC using a C18 column and a mixture of MeCN and water modified with 0.1% TFA. The product-containing fractions were partitioned between pH 4 buffer (20 mL) and EtOAc (20 mL) and the layers were separated. The aqueous phase was extracted with EtOAc (1×20 mL)), then the combined organic phases were washed with brine (20 mL), dried, and concentrated to yield 1-bromo-5-hydroxy-5-(5-(4-methyl-6-((4-(trifluoromethyl)pyridin-2-yl)amino)pyridin-2-yl)thiazol-2-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (25 mg, 52%) as a white solid. MS ESI calcd for C26H20BrF3N4O3S [M+H]+ 605, found 605. 1H NMR (600 MHz, dmso) δ 10.17 (s, 1H), 8.62 (s, 1H), 8.46 (d, J=5.0, 1H), 8.20 (s, 1H), 7.35-7.29 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.68 (s, 1H), 2.79 (s, 3H), 2.32-2.2.24 (m, 4H), 2.06 (br s, 1H), 1.96 (br s, 2H) ppm.
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(OC([NH:26][C@@H:27]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH3:33])[CH3:32])[C:28](O)=[O:29])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.O1CCOCC1>CN(C=O)C>[ClH:40].[ClH:1].[NH2:26][C@H:27]([C:31]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)([CH3:33])[CH3:32])[C:28]([N:6]1[CH2:7][CH2:8][N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:5]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)c1ccc(Cl)cc1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(c1ccc(Cl)cc1)[C@@H](N)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reaction time: 8 h
Yield: 145.6 %

Procedure:
The 4-piperazin-1-yl-quinazoline bis-hydrochloride (220 mg, 0.766 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-3-methyl-butyric acid (251 mg, 0.766 mmol, 1.0 equiv), 1-hydroxybenzotriazole (109 mg, 0.804 mmol, 1.05 equiv), and EDCI (154 mg, 0.804 mmol, 1.05 equiv) were dissolved/suspended in 6.0 mL of DMF. The mixture was treated with triethylamine (427 μL, 3.06 mmol) and allowed to stir overnight to completion. The reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was eluted through a small plug of silica gel with ethyl acetate and concentrated in vacuo. The protected intermediate was immediately dissolved in 1 mL of dioxane and treated with 4M HCl in dioxane (1.92 mL, 7.66 mmol) at room temperature for four hours. The resulting precipitate was triturated with ether, then filtered to afford the (R)-2-amino-3-(4-chlorophenyl)-3-methyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-butan-1-one bis-hydrochloride as a light-yellow solid (277 mg, 73%) upon drying under vacuum. 1H NMR (DMSO-d6, 400 MHz) δ 8.89 (s, 1H), 8.46 (brs, 3H), 8.17 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.53 (brs, 1H), 4.09 (m, 3H), 3.90 (m, 3H), 3.32 (m, 1H), 3.04 (t, J=9.2 Hz, 1H), 1.51 (s, 3H), 1.43 (s, 3H). LCMS (APCI+) m/z 424 [M+H]+; Rt=1.90 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:23]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CC2CSc3ccccc3C2=NN1c1ccc(Cl)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC2CS(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of 11.5 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one in 200 ml of acetic acid is added 66 ml of 35% hydrogen peroxide dropwise with stirring at room temperature. After the completion of addition, the mixture is stirred at room temperature for 3 hours, poured into an excess amount of water and extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off under reduced pressure. To the precipitated crystals is added diisopropyl ether. The crystals are collected by filtration and recrystallized from isopropyl alcohol to give 7.7 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6-oxide, melting at 181°-183° C., as colorless needles.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N-:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].FC(F)(F)C1C(C2C=C3C(C(O)=NC=N3)=CC=2)=NC=CC=1>>[ClH:1].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([C:23]4[C:28]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc([N-]c2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Agent: Cl
Agent: Oc1ncnc2cc(-c3ncccc3C(F)(F)F)ccc12
Product: CC(C)(C)c1ccc(Nc2ncnc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1

Procedure:
Using procedures analogous to those described above (see, for example, Schemes 1 and 2), (4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-amide hydrochloride is prepared from 7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol in two steps. Mass spec. 422.2.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[O:10][C:11]([C:13]1[C:18]([CH2:19][CH:20]=O)=[CH:17][C:16]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:15][N:14]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:11](=[O:10])[C:13]3[N:14]=[CH:15][C:16]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][C:18]=3[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1ncc(COc2ccccc2)cc1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1c2ncc(COc3ccccc3)cc2CCN1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.2 %

Procedure:
4-Fluoroaniline (0.032 mL, 0.34 mmol) was added to a stirred solution of 3-(2-oxo-ethyl)-5-phenoxymethyl-pyridine-2-carboxylic acid methyl ester (80 mg, 0.28 mmol, from step 7) in DCM (4 mL). The mixture was stirred at RT for 1 h. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and the mixture was stirred at RT for 16 h. Acetic acid (0.040 mL) was added and the mixture was stirred at RT for additional 20 h. The mixture was diluted with DCM and washed with a saturated solution of NaHCO3 and brine. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 4/96). The desired fractions were collected and the solvents evaporated in vacuo to yield an impure fraction which was re-purified by RP-HPLC on (C18 XBridge, 19×100, 5 μm; 80%/0.1% NH4CO3H/NH4OH pH 9 solution in water, 20% CH3CN to 0%/0.1% NH4CO3H/NH4OH pH 9 solution in water, 100% CH3CN), to yield 7-(4-fluoro-phenyl)-3-phenoxymethyl-6,7-dihydro-[1,7]-naphthyridin-8(5H)-one (14.86 mg, 15% yield) as a white solid: 1H NMR (500 MHz, CDCl3) δ 3.22 (t, J=6.4, 2 H), 4.01 (t, J=6.4, 2 H), 5.17 (s, 2 H), 6.98 (d, J=7.8, 2 H), 7.01 (t, J=7.5, 1 H), 7.07-7.16 (m, 2 H), 7.29-7.35 (m, 2 H), 7.36-7.42 (m, 2 H), 7.76 (br. s, 1 H), 8.78 (d, J=1.7, 1 H); LC-MS (M+H)=349.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].Cl>O.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[C:17](=[O:18])[NH:16][C:15]4[CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=[CH:22][C:14]=4[NH:13][C:12]=3[CH:27]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccnc(F)c3)cc1N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)NC(=O)c1ccc(-c3ccnc(F)c3)cc1N2
Yield: 79.1 %

Procedure:
A mixture of Example 69B (60 mg, 0.17 mmol) and LiOH (20 mg, 0.85 mmol) in water (5 mL) and THF (5 mL) was heated to reflux until a homogeneous solution formed, adjusted to pH 5 with 10% HCl, and extracted with ethyl acetate several times. The combined extracts were washed with brine, dried (CaCl2), filtered, and concentrated under vacuum to provide 47 mg (80%) of the desired product. MS (DCI) m/e 349 (M)+; 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.42 (s, 1H), 8.36 (d, J=5.3 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.62 (d, J=5.3 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.55 (dd, J=8.4, 1.9 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J=1.6 Hz, 1H), 7.37 (dd, J=8.1, 1.9 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:21]([C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)(=[O:23])=[O:22])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1cnc(N2CCNCC2)s1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3cccs3)CC2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane (7.5 mL) were added 2-thiophene sulfonyl chloride (241 mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 4 h. Water (10 mL) followed by dichloromethane (10 mL) were added to the reaction mixture and the organic layer was separated, dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 12i as a solid (300 mg, 91.4%). HPLC: 99.74% (Rt=7.22 min).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:12]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH:22]2[O:24][CH2:23]2)=[CH:18][CH:17]=1)(=[O:14])[CH3:13].O>CS(C)=O>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[NH:1][CH2:23][CH:22]([OH:24])[CH2:21][O:20][C:19]1[CH:25]=[CH:26][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:17][CH:18]=1
Reactant: NC1CCc2ccccc2C1
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC2CCc3ccccc3C2)cc1
Temperature: 80 °C
Yield: 35.7 %

Procedure:
A mixture of 2-aminotetralin (2.5 g) and 1-(4-acetamidophenoxy)-2,3-epoxypropane (3.52 g) in dimethylsulfoxide (40 ml) is heated at 80° C. for 5 hours. The reaction mixture is allowed to cool toat room temperature and water (180 ml) is then added thereto. The precipitate which forms is recovered by filtration and crystallized from absolute ethanol (120 ml) yielding 2.15 g of N-(1,2,3,4-tetrahydronaphth-2-yl)-2-hydroxy-3-(4-acetamidophenoxy)-propanamine; m.p. 133°-136° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]CS([O-])(=O)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:19]([NH:26][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(CCCS(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CCNCc2ccccc2)cc1

Procedure:
2-(4-Methanesulfonamidophenyl)ethylmethanesulfonate (XXXII) (20 g), benzylamine (7.0 g) and triethylamine (15 ml) were combined in dimethylformamide (75 ml) and heated 18 hours at 100°. The solvent was evaporated and the residue was dissolved in EtOAc, which was washed with saturated NaHCO3, dried (MgSO4) and evaporated to give a dark oil. This was chromatographed on a silica column, eluting 8.0 g of solid product with CHCl3 /MeOH/concentrated NH4OH (15:1:0.1). This solid was treated with MeOH/concentrated HCl (10:1), causing precipitation of 4'-(2-benzylaminoethyl)methanesulfonanilide.HCl (XXIX.HCl), m.p. 244°-245°, whose NMR was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.CN(C1C=CC=CN=1)C.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][N:49]=1>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[C:52]([C:51]2[CH:50]=[N:49][C:48]([Cl:47])=[CH:56][CH:55]=2)=[O:53])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)c2ccc(Cl)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (53 mg, 0.125 mmol), diisopropylethylamine (64.7 mg, 0.50 mmol), dimethylaminopyridine (3 mg, 0.024 mmol, Aldrich) in CH2Cl2 (6 mL) and 6-chloro-nicotinoyl chloride (41.0 mg, 0.232 mmol, Aldrich) was stirred at room temp. for 2 hrs before diluted with EtOAc, washed with aqueous Na2CO3, brine, and concentrated. The residue was purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(6-chloro-pyridine-3-carbonyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (58.3 mg, 83%) as a white solid. HRMS (ES+) m/z Calcd for C28H24Cl3F2N3O+H [(M+H)+]: 562.1026; Found: 562.1026
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=[N:31]O)[NH2:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[S:34].B(F)(F)F.CC[O:51]CC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:30][C:33](=[O:51])[S:34][N:31]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(N)=NO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: C1CCOC1
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2nsc(=O)[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 83 mg (0.17 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide (Example 82, Step C) in THF (4 mL) was added 50 mg (0.28 mmol) of 1,1′-thiocarbonyldiimidazole. The resulting yellow solution was stirred at room temperature for 1 h, and then was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was dissolved in THF (4.5 mL), and 69 μL (0.56 mmol) of boron trifluoride etherate was added via syringe. The resulting light yellow solution was stirred at room temperature for 2.5 h, and then was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 55% MeCN in water to 85% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>[Pd].C(O)C>[OH:13][CH2:12][CH2:11][CH2:10][N:9]1[CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]1[CH3:6]
Reactant: CC(=O)CCC(C)=O
Reactant: NCCCO
Agent: [Pd]
Solvent: CCO
Product: CC1CCC(C)N1CCCO
Reaction time: 3 h
Yield: 36 %

Procedure:
A total of 3 moles of 2,5-hexanedione, 3 moles of 3-amino-1propanol, 10 g of 10% Pd/C, and 500 ml of ethanol were charged to an autoclave. The reaction mixture was pressured up to 1100 psi of H2 and kept for 3 hours at 100° C. Distillation yielded 170 g of N-(3-hydroxypropyl)-2,5-dimethylpyrrolidine (b.p.=119° C. at 25 mm).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[O:11]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[OH:11]
Reactant: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: COC(=O)C(CC1CCCC1O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 101.2 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-[2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (prepared as in Example 24, 2.3 g, 5.73 mmol) in ethanol (57.3 mL) at 25° C. was treated with pyridinium p-toluenesulfonate (144 mg, 0.57 mmol). The resulting solution was heated under reflux for 18 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 50/50 hexanes/ethyl acetate) afforded 2-(3,4-dichloro-phenyl)-3-(2-hydroxy-cyclopentyl)-propionic acid methyl ester (1.84 g, 100%) as a clear oil: EI-HRMS m/e calcd for C15H18Cl2O3 (M+Na)+ 339.0527, found 339.0528.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:31])[CH:8]=1.Cl.O>C1COCC1>[F:31][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[C:13]1[S:14][C:15]2[C:20]([N:21]=1)=[CH:19][CH:18]=[C:17]([C:22]1([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][CH2:24]1)[N:16]=2)[CH:2]=[O:1]
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine (22.3 g, 51.6 mmol) in 200 mL THF was added 200 mL 5N HCl. The reaction mixture became warm, was fitted with a water-cooled reflux condenser, and was heated to 65° C. in an oil bath under argon. After 3 h, the reaction was nearly homogeneous. The bath was turned off and the reaction allowed to stir overnight. In the morning a nice yellow precipitate was evident. The THF was removed in vacuo, and the resulting slurry was filtered, rinsing with water, and dried under nitrogen, then dried in vacuo overnight to give 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde as a light orange solid. MS (ESI) m/z: Calculated: 374.1; Observed: 375.1 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].C([Na])#N.[NH2:27][C:28]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:29]=1[CH:30]([OH:46])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:32]=1>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:27][C:28]2[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][C:29]=2[CH:30]([OH:46])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[CH:32]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2N)c1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: N#C[Na]
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(C(O)c2cc(Cl)ccc2NCC2CCN(C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C

Procedure:
3,5-Trans-N-(2-fluorobenzyl)-1-(N-benzyloxycarbonylpiperidin-4-yl-methyl)-5-(3-tert-butoxycarbonylaminomethylphenyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide (1) In methanol (20 ml) were dissolved 2-amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol produced in Example 1-(2) (1.0 g) and N-benzyloxycarbonyl piperidine-4-carbaldehyde (0.82 g), followed by addition of acetic acid (0.2 g). To the mixture was added, while stirring at room temperature, cyano sodium borohydride (0.2 g). The reaction mixture was stirred for 30 minutes at 60° C., which was then concentrated. To the concentrate was added water (40 ml), followed by extraction with ethyl acetate (60 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by means of a silica gel column chromatography to give 2-(N-benzyloxycarbonylpiperidin-4-yl-methyl)amino-5-chloro-α-(3-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (1.5 g) as a colorless oily product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH3:23]>CCO>[NH2:23][CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: N
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: CCO
Product: CCOC(=O)C(=CN)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
12.8 g of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl)-acrylate are initially introduced into 16 ml of EtOH. A mixture of 3.3 ml of concentrated aqueous NH3 solution and 10 ml of EtOH is added dropwise with ice cooling. The mixture is subsequentially stirred for 2 hours. Ice-water is then added, and the precipitated solid is filtered off under suction.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[Cl-].[Al+3].[Cl-].[Cl-].[Al].[CH2:16]=[CH2:17]>>[CH2:16]([C:10]1[C:2]([NH2:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH2:5][CH2:4]2)[CH3:17]
Reactant: Nc1cccc2c1CCC2
Reactant: C=C
Agent: [Al+3]
Agent: [Al]
Agent: [Cl-]
Product: CCc1ccc2c(c1N)CCC2
Temperature: 300 °C

Procedure:
A mixture of 106 g (0.8 mole) of 4-amino-indane, 4 g of aluminium chloride and 1.6 g of aluminium shot is heated in an autoclave to 300°C. After injection of ethylene at 200 bar, the reaction mixture is maintained for one hour at 300°C. By distillation of the green-black crude product in high vacuum there is obtained 106.9 g of 5-ethyl-4-amino-indane, B.P. 72 to 74°C/0.001 Torr.