Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[C:19](=[O:23])[CH2:18][CH2:17][C:16]([CH3:25])([CH3:24])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:20]3[CH:19]([OH:23])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:25])[C:15]=3[CH:14]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl[4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 4) in 5 mL MeOH at 0° C. was added NaBH4 (18.0 mg, 0.48 mmol). The reaction was stirred at 0° C. for 2 hours and then quenched by the addition of H2O. The solution was diluted with Et2O and washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and the solvents were removed under reduced pressure. Column chromatography (20-40% lEtOAc-hexanes) afforded 140.0 mg (87%) of the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1.[I-:14].[Na+]>CC(C)=O>[I:14][CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: [I-]
Reactant: ClCCc1ccc2c(c1)OCCO2
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCc1ccc2c(c1)OCCO2
Yield: 77.8 %

Procedure:
A solution of (a) (0.22 g) in acetone (10 ml) was treated with sodium iodide (0.6 g) and heated to reflux overnight. The mixture was filtered and evaporated. The residue was partitioned between dichloromethane and dilute aqueous sodium sulphite solution. The organic extract was dried and evaporated to give a brown oil (0.25 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23]Br)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[CH:18]([O:27][C:28](=[O:30])[CH3:29])[CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2].[NH:34]1[CH:38]=[CH:37][CH:36]=[N:35]1>CN1CCCC1.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[C:22]([CH2:23][N:34]3[CH:38]=[CH:37][CH:36]=[N:35]3)=[CH:21][C:20]3[C:19]([CH3:26])([CH3:25])[CH:18]([O:27][C:28](=[O:30])[CH3:29])[CH2:17][C:16]([CH3:32])([CH3:31])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2CBr)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Reactant: c1cn[nH]c1
Agent: CN1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2Cn2cccn2)C(C)(C)C(OC(C)=O)CC3(C)C)cc1
Temperature: 25 °C
Yield: 7263.6 %

Procedure:
A solution of 0.45 g (0.88 mmol) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3-bromomethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate and 0.24 g (3.5 mmol) of pyrazole in 15 mL of N-methyl pyrrolidine was heated to 100° C. After 2 hours the reaction was cooled to room temperature, poured into brine and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution, hexane-16% ethyl acetate/hexane) to afford 32 g (73%) of ethyl-4-[(E)-2-(5,5,8,8-tetramethyl-3pyrazol-1-ylmethyl-6-acetoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoate (M+=500).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](C(N2C(CC3CCCCC3)C(=O)N3CC4C=CC=CC=4CC3C2=O)C(NCCC2C=CC(F)=CC=2)=O)=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:46]>>[C:1]([NH2:2])(=[O:46])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C(C(=O)NCCc2ccc(F)cc2)N2C(=O)C3Cc4ccccc4CN3C(=O)C2CC2CCCCC2)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
This compound was prepared by stirring 2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-N-[2-(4-fluoro-phenyl)-ethyl]-acetamide (305 mg, 0.51 mmol) in 10 ml of concentrated sulfuric acid. After 1 hour the solution was poured into 40 g of ice. The ice melted and the white solid was filtered, dried, and the crude product was purified by flash chromatography (1:20 methanol/dichloromethane; Rf =0.25) to give 60 mg (20%) of 4-{(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-[2-4-fluoro-phenyl)-ethylcarbamoyl]-methyl}-benzamide.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14].Cl.C=O>>[PH:1](=[O:2])([OH:4])[OH:3].[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14]
Reactant: OP(O)O
Agent: C=O
Agent: Cl
Agent: NCCNCCNCCN
Product: O=[PH](O)O

Procedure:
To a 1 liter 5 neck flask fitted with a reflux condenser and dropping funnel is added 234.3 grams (2 mole) 70% phosphorous acid. Triethylenetetramine, 146 grams (1 mole) is then added dropwise while stirring, followed by 146 grams (4 moles) anhydrous HCl. The mixture is then heated to reflux and 162.2 grams (2 moles) 37% aqueous formaldehyde is added dropwise over 1 hour. Reflux is maintained for 2 hours after formaldehyde addition is complete, after which the reaction mixture containing the amino methylene phosphonic acid product is cooled and bottled.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2ccncn2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccncn3)nc3ccccc13)C2
Yield: 17 %

Procedure:
Reaction of 2-(4-pyrimidinyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 72 (17% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.86 and 3.13 (2t, 2H), 3.54 and 4.17 (2t, 2H), 3.81-3.90 (m, 6H), 4.43 and 5.06 (2s, 2H), 6.51 and 6.91 (2d, 1H), 6.71 and 7.01 (2d, 1H), 7.74-7.81 (m, 2H), 8.04-8.13 (m, 2H), 8.39-8.41 (2s, 1H), 8.65-8.70 (m, 1H), 9.04-9.06 (m, 1H), 9.57 (s, 1H); MS (ESI) m/z 428 ([M+H]+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>C(#N)C.CCOC(C)=O>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([C:1]#[C:2][CH2:3][CH3:4])[CH:18]=1
Reactant: C#CCC
Reactant: Brc1cncc(Br)c1
Solvent: CC#N
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
But-1-yne (g) was during 5 min gently bubbled through anhydrous acetonitrile cooled in an ice-water bath. The resulting solution contained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57 mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were added sequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol), bis(triphenylphosphine)-palladium(IT) chloride (0.458 g, 0.65 mmol) and CuT (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc and passed through a short plug of silica. The solvents were evaporated and the residue was purified by flash chromatography on silica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of the title compound (87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 4 H), 2.47 (q, 3 H), 8.11 (t, 1 H), 8.57 (d, 1 H), 8.65 (d, 1 H); MS (ES+) m/z 210 [M+H]F.
Reaction SMILES: [O:1]1[CH2:6][C:5](=S)[NH:4][C:3](=[O:8])[NH:2]1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCOCC1>[N:9]1([C:5]2[CH2:6][O:1][NH:2][C:3](=[O:8])[N:4]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C1NOCC(=S)N1
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: O=C1N=C(n2ccnc2)CON1
Temperature: 25 °C
Reaction time: 17 h
Yield: 56.2 %

Procedure:
To a solution of 1.0 g (0.0075 mole) of 6H-1,2,4-oxadiazin-3(2H)-one-5(4H)-thione in 50 ml of freshly distilled dry dioxane is added 0.52 g (0.0077 mole) of imidazole. After stirring at room temperature for 17 hours, the solution is filtered, washed with chloroform and dried to give a yield of 0.7 g (56 percent) of 5-(1H-imidazol-1-yl)-6H-1,2,4-oxadiazin-3(2H)-one.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[CH2:4][N:5]([CH:29]([CH3:31])[CH3:30])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24](OC)[O:25]C)[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[I-].[Na+].ClC([SiH3])(Cl)Cl>>[F:1][C:2]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:3]=1[CH2:4][N:5]([CH:29]([CH3:31])[CH3:30])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:19][CH2:20][CH:21]([CH:24]=[O:25])[CH2:22][CH2:23]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(OC)C1CCN(S(=O)(=O)c2ccc(NC(=O)N(Cc3cc(F)ccc3F)C(C)C)cc2)CC1
Agent: [I-]
Agent: [Na+]
Agent: [SiH3]C(Cl)(Cl)Cl
Product: CC(C)N(Cc1cc(F)ccc1F)C(=O)Nc1ccc(S(=O)(=O)N2CCC(C=O)CC2)cc1

Procedure:
The title compound was prepared from 1-(2,5-difluoro-benzyl)-3-[4-(4-dimethoxymethyl-piperidine-1-sulfonyl)-phenyl]-1-isopropyl-urea (0.530 g, 0.001 mol), sodium iodide (0.188 g, 1.26 mmol), and trichloromethylsilane (0.118 mL, 1.0 mmol) according to the procedure used for example 84 (Step D) and used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]O)=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1O
Reactant: OCCCc1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A mixture of 0.070 g of 4-chloro-7-hydroxy-6-methoxy-quinoline-3-carbonitrile, 0.062 g of 3-(4-pyridyl)-1-propanol and 0.235 g of triphenylphosphine in 3 ml of methylene chloride under nitrogen was cooled to 0° C. To this was added 0.14 ml of diethyl azodicarboxylate dropwise. After 30 minutes, the reaction mixture was warmed to room temperature and further stirred for 2 hours. The mixture was concentrated down to 1 ml and purified by silica gel chromatography, eluting with a solvent gradient of 1 to 2 percent methanol/methylene chloride, to provide 0.090 g of 4-chloro-6-methoxy-7-(3-pyridin-4-yl-propoxy)-quinoline-3-carbonitrile as an off-white gum.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:8]=1[Cl:34])[CH3:6])=[O:4].[CH3:35][O:36][C:37]([NH:39][C:40]1[N:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48](O)=[O:49])=[CH:42][CH:41]=1)=[O:38].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[Cl:34][C:8]1[C:9]([CH2:14][O:15][C:16]2[C:24]3[N:23]=[C:22]([O:25][CH3:26])[N:21]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:20]=3[CH:19]=[CH:18][CH:17]=2)=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[N:5]([CH3:6])[C:3](=[O:4])[CH2:2][NH:1][C:48](=[O:49])[CH2:47][CH2:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:37](=[O:38])[O:36][CH3:35])=[N:45][CH:44]=1
Reactant: COC(=O)Nc1ccc(CCC(=O)O)cn1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1Cc1ccccn1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: COC(=O)Nc1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cn1

Procedure:
2-amino-N-(2,4-dichloro-3-(((2-methoxy-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazol-4-yl)oxy)methyl)phenyl)-N-methylacetamide and 3-(6-((methoxycarbonyl)amino)pyridin-3-yl)propanoic acid were combined as previously described for compound 1 to give 2. LCMS (+APCI) 706 (M+). 1H-NMR (CDCl3, δ ppm): 8.58 (m, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.72 (bs, 1H), 7.58 (dt, J=1.6, 7.6 Hz, 1H), 7.51 (2.0, 8.4 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.19 (m, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.40 (bt, 1H), 5.67 (d, J=1.6 Hz, 2H), 5.28 (s, 2H), 4.21 (s, 3H), 3.78 (s, 3H), 3.75 (m, 1H), 3.50 (dd, J=4.0, 17.6 Hz, 1H), 3.23 (s, 3H), 2.88 (dd, J=7.6 Hz, 2H), 2.49 (t, J=7.6 Hz, 2H). Calcd. for C34H33Cl2N7O6+1H2O: C, 56.36; H, 4.87; N, 13.53. Found: C, 56.34; H, 4.68; N, 13.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1>>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Product: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Yield: 67.8 %

Procedure:
Following Example 188c, 327b (2.6 g, 9.4 mmol) and 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.5 g, 9.4 mmol) were reacted to give 327c as a yellow solid (2.96 g, 68%). MS: [M+H]+ 464.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([OH:12])(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([Cl:20])(=O)CCCCC.C=O>>[C:5]([O:12][CH2:13][Cl:20])(=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC(=O)O
Reactant: CCCCCC(=O)Cl
Agent: C=O
Solvent: O=S(Cl)Cl
Product: CCCCCC(=O)OCCl
Temperature: 70 °C

Procedure:
Thionyl chloride (14.27 g, 0.12 mmol) was added dropwise to hexanoic acid (11.61 g, 0.10 mmol) and the reaction mixture was heated at 70° C. for 24 hours. The reaction mixture containing hexanoyl chloride was not further purified and paraformaldehyde (3.60 g, 0.12 mol) was added and the reaction mixture heated at 120° C. until the latter disappeared (about 2 hours). The reaction mixture was distilled in vacuo and chloromethyl hexanoate was obtained as a colourless oil (b.p. 118° C., 25 mbar). 1H-NMR (CDCl3) δ 5.67 (s, 2H), 2.37-2.29 (m, 2H), 1.65-1.58 (m, 2H), 1.31-1.26 (m, 4H), 0.88 (t, 3H). 13C-NMR(CDCl3) δ 179.89, 171.77, 68.53, 33.95, 31.18, 24.34, 22.26, 13.83.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][N:13]([CH2:25][C:26]2[C:31]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])[C:12]1=[O:37])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C@H:9]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:10][N:11]1[C:16](=[O:17])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][N:13]([CH2:25][C:26]2[C:31]([C:32]([F:34])([F:33])[F:35])=[CH:30][CH:29]=[CH:28][C:27]=2[F:36])[C:12]1=[O:37]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(-c2ccccc2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cn1c(=O)c(-c2ccccc2Cl)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
To a solution of compound 6e (0.144 g, 0.23 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.5 mmol) and the mixture was stirred at room temperature for 1.5 hours. After concentration, the residue was taken up in DCM and sat'd aq. NaHCO3 was added. The aqueous layer was extracted with DCM. Combined organic extracts were dried over Na2SO4 and concentrated to give compound 6f (0.12 g). MS (CI) m/z 518.0, 520.1 (MH+).
Reaction SMILES: [Mg].[O:2]=[C:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](Cl)=[O:20].S(=O)(=O)(O)O>CCOCC.C(Cl)(Cl)(Cl)Cl.C(O)C>[C:3]([CH:4]([C:19](=[O:20])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:2])[CH3:10]
Reactant: Cc1ccccc1CC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C(C)=O)C(=O)Cc1ccccc1C
Reaction time: 8 h

Procedure:
This material was prepared according to the procedure of M. Viscontini and N. Merckling, Helvetica Chimica Acta, 35, 2280 (1952). To 2.65 parts of magnesium turnings was added 15 parts absolute ethanol at room temperature and 0.5 parts of carbon tetrachloride. As soon as the initial reaction subsides 100 parts of dry ether was added. The mixture was stirred without cooling until the reaction ceased, then 19.6 parts of ethyl 3-oxobutanoate in 20 parts of dry ether was added with ice cooling and good stirring. After the resulting precipitate dissolved, the solution was cooled in an ice-salt bath and 16 parts of 2-methylphenylacetyl chloride was slowly added. The mixture was allowed to stand overnight at room temperature and then combined with ice and sulfuric acid. The ether layer was separated, washed with water, dried over sodium sulfate and stripped to give ethyl 2-acetyl-4-(2-methylphenyl)-3-oxobutanoate as a crude oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Cc1ccc(Br)c2c1NCC2
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4c(Br)ccc(C)c43)ncnc2c1
Yield: 69 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 69% yield from 4-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 134°-135° C.; LC-MS: 370, 372 (MH+); anal. RP18-HPLC RT: 5.60 min.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24].CO.I([O-])(=O)(=O)=[O:29].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:20])=[O:29])=[CH:15][CH:14]=1)[C:6]([CH3:21])=[C:5]2[CH2:22][C:23]([OH:25])=[O:24]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C=C2C(C)=C(CC(=O)O)c3cc(F)c(F)cc32)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)c2cc(F)c(F)cc2C1=Cc1ccc(S(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.358 g (1.0 mmol) of 5,6-difluoro-2-methyl-1-(p-methylthiobenzylidene)-indene-3-acetic acid in acetone (10 ml) is added 10-15 ml MeOH. With magnetic stirring 0.32 g (1.5 mmol) of sodium meta periodate is added in 5 ml of water. The proportions of acetone, methanol and water are adjusted if necessary in order to preserve homogeneity. After several minutes, a precipitation of sodium iodate appears. The suspension is stirred at room temperature for 16 h, and is then poured into approximately 50 ml of water and 100 ml methylene chloride. The two phases are separated and extracted twice with methylene chloride. The organic layer is washed with water and dried (MgSO4). The residue after evaporation is dissolved in the minimum amount of boiling ethyl acetate and is allowed to stand for 12 h in the freezer compartment. The deep orange crystals are filtered. The filtrate is reduced to 1/2 volume and allowed to stand in the cold for several hours to give a large second crop. In this way, 5,6-difluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid is isolated, m.p. 200°-210° C.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36]CC4C=CC=CC=4)=[C:32]([F:44])[CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CCOC(C)=O.CC(O)=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:44])[CH:31]=3)[OH:29])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(OCc3ccccc3)c(F)c2)c1)C1CCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c(F)c2)c1)C1CCCC1
Reaction time: 4 h

Procedure:
To an evacuated flask containing palladium on carbon [50% water by weight] was added a solution of (1R)-2-{[6-({4-[3-(cyclopentylsulfonyl)phenyl]butyl}oxy)hexyl]amino)-1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}ethanol (37 mg) in EtOAc (8 ml) and AcOH (2 ml). The reaction mixture was hydrogenated for 4 h. The catalyst was filtered off and the filtrate concentrated in vacuo to give the title compound. LCMS RT=2.60 min 535(M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:24][OH:25])([CH2:22][OH:23])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:33]1([CH2:39][CH2:40][CH2:41][CH2:42]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]([CH2:22][OH:23])([CH2:24][OH:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:42][CH2:41][CH2:40][CH2:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:13]([C:18]([F:20])([F:19])[F:21])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(O)c(C(F)(F)F)c1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO)(CO)CCc1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 103.8 %

Procedure:
Compound 3-6 (350 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (255 mg) and 4-phenylbutylbromide (235 mg) were added, and the mixture was stirred at 80° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (490 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]2=[O:19].[CH3:20][C:21]([NH2:24])([CH3:23])[CH3:22]>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:24][C:21]([CH3:23])([CH3:22])[CH3:20])[N:8]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:7]2=[O:19]
Reactant: CC(C)(C)N
Reactant: O=c1c2cccc(Br)c2nc(Cl)n1C1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CCOCC1
Yield: 12.4 %

Procedure:
A solution of 8-bromo-2-chloro-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515c, 0.51 g, 1.484 mmol) and 2-methylpropan-2-amine (Sigma-Aldrich Co., 3.12 mL, 29.7 mmol) in NMP (7.42 mL) was stirred at 100° C. for 16 h. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with water (3×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 60% EtOAc in hexanes to give 8-bromo-2-(tert-butylamino)-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515d, 70 mg, 0.184 mmol, 12.40% yield) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 9H) 1.77 (dd, J=12.52, 2.54 Hz, 2H) 2.41 (qd, J=12.52, 4.69 Hz, 2H) 3.58 (td, J=11.74, 1.96 Hz, 2H) 4.14 (dd, J=12.23, 4.21 Hz, 2H) 4.70 (s, 1H) 5.48 (t, J=12.72 Hz, 1H) 6.97 (t, J=7.82 Hz, 1H) 7.83 (dd, J=7.63, 1.37 Hz, 1H) 8.04 (dd, J=8.02, 1.37 Hz, 1H). MS (ESI, pos. ion) m/z: 380.2/382.2 (M+1).