Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1>C(Cl)(Cl)Cl.C(O)(C)C.[OH-].[Na+]>[CH2:4]([O:3][C:1]([NH:12][C@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN1C[C@@H](N)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CN1C[C@@H](NC(=O)OCc2ccccc2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.5 ml (75 mM) carbobenzyloxychloride are added to a suspension of 18 g (74.7 mM) 8α-amino-6-methylergoline in 1000 ml chloroform, 150 ml isopropanol and 37 ml 2N (74 mM) sodium hydroxide at room temperature. The mixture is stirred for 2 hours at room temperature. After separation of the organic phase, this is dried, filtered and concentrated. The resultant crude product is filtered through silicagel with methylene chloride/methanol (99:1) giving the heading compound as a foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[CH:3]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11]>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[Cl:8][C:4]1[CH:3]=[C:2]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CC(C)(C)O
Reactant: Clc1cccc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 93.8 %

Procedure:
Add triethylamine (75 mL), 1-bromo-3-chlorobenzene (24.1 g, 0.126 mol), and 2-methylbut-3-yn-2-ol (15 mL, 0.152 mol) to a degassed mixture of bis(triphenylphosphine)palladium (II) dichloride (49 mg, 7.1 10−5 mol) and copper (I) iodide (2.4 mg, 1.26 10−5 mol). Stir at 90° C. for 72 h. Cool the reaction mixture to room temperature. Filter, concentrate and dissolve in ethyl acetate. Wash with water and dry the organic phase over sodium sulfate. Filter, concentrate and purify the residue by silica gel chromatography, eluting with hexane:ethyl acetate 6:1, to give the title compound (23 g, 94%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.Br[CH2:13][C:14](=[N:19][OH:20])[C:15]([O:17][CH3:18])=[O:16]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]23[CH2:11][CH2:10][CH2:9][CH:8]2[CH2:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:19][O:20]3)[CH2:3][CH2:2]1
Reactant: C1CCC(N2CCOCC2)C1
Reactant: COC(=O)C(CBr)=NO
Product: COC(=O)C1=NOC2(N3CCOCC3)CCCC2C1
Yield: 70.8 %

Procedure:
4.6 g (30 mmol) of morpholinocyclopentane are reacted with 1.75 g (10 mmol) of methyl 3-bromohydroxyiminopropionate by following the method of Example 1(a). 1.9 g of a colorless oil are obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:18][C@H:17]([NH2:19])[CH2:16][C@H:11]2[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:15][O:14][C:12](=[O:13])[C@@H:11]1[CH2:16][C@@H:17]([NH:19][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][N:10]1[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)CCCCCNC(=O)OC(C)(C)C)CN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a mixture of 300 mg of 18 (1.06 mmol), 244 mg (1.06 mmol) of 6-(Boc-amino)-caproic acid (Bachem), and 485 mg (1.27 mmol, 1.2 equiv.) of HATU in 4 mL of DMF was added 525 μL (3.0 mmol, ˜3 equiv.) of diisopropylethylamine. The resulting mixture was stirred at room temperature overnight, then diluted with ˜100 mL EtOAc and washed with 1 N HCl (three times), 1 N NaOH (twice), then brine, and dried (MgSO4), filtered, and concentrated to an orange oil. This was dissolved in CH2Cl2, loaded onto silica, and eluted with 3:2 CH2Cl2/CH3CN to give 308 mg (0.62 mmol, 58%) of 19 as a foamy white solid. 1H-NMR (400 MHz, CDCl3, 6 ppm) 7.90 (dd, J=1 Hz, 8 Hz, 2H), 7.60 (tt, J=1 Hz, 8 Hz, 1H), 7.53 (tt, J=1 Hz, 8 Hz, 2H), 5.71 (d, J=6 Hz, 1H), 4.58 (br s, 1H), 4.53 (t, J=8Hz, 1H), 4.47 (m, 1H), 3.66 (s, 3H), 3.54 (q, J=5 Hz, 1H), 3.39 (dd, J=3 Hz, 11 Hz, 1H), 3.08 (m, 2H), 2.24 (m, 2H), 2.02 (t, J=8 Hz, 2H), 1.56 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H), 1.28 (m, 2H); 13C-NMR (400 MHz, CDCl3, 8 ppm) 173.21, 172.19, 164.53, 138.83, 133.62, 129.58, 128.04, 123.12, 59.13, 53.70, 52.97, 49.68, 40.68, 37.47, 36.59, 30.08, 28.82, 26.64, 25.38; m/z: 498 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]([OH:8])[CH3:7])[N:3]=[N:2]1.N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>C(Cl)Cl>[Si:18]([O:8][CH:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)[CH3:7])([C:15]([CH3:17])([CH3:16])[CH3:14])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1c[nH]nn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1c[nH]nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a solution of 1-(1H-1,2,3-triazol-4-yl)ethanol (50.2 mmol) and imidazole (5.13 mg, 75 mmol) in DCM (50 ml) 0° C. was added TBDPSCl (14.6 mL, 55.2 mmol). After stirring at room temperature overnight the mixture was filtered through a celite pad and then concentrated to dryness. The resulting residue was dissolved in EtOAc, washed with water, brine, dried with sodium sulfate and concentrated. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 5-25%) afforded the title compound (8.16 g, 46%) as a yellow oil. LCMS: Rt=1.09 min, m/z=352.1 (M+1) Method 2m_acidic. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=6.5 Hz, 2H) 7.64-7.54 (m, 3H) 7.49-7.28 (m, 6H) 5.14 (q, J=6.3 Hz, 1H) 1.46 (dd, J=6.3, 3.0 Hz, 3H) 1.08 (s, 9H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)C.[O:8]1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9]1>O>[OH:2][CH2:1][CH2:3][NH:4][CH2:9][CH:10]([OH:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCC1CO1
Reactant: NCCO
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCC(O)CNCCO
Temperature: 80 °C
Yield: 74.6 %

Procedure:
A 300-ml flask equipped with a stirrer and a dropping funnel was charged with 45.8 g (0.75 mol) of ethanolamine and 9 g of ethanol. While stirring the mixture at 80° C., 13.4 g (50 mmol) of 1,2-epoxyoctadecane were added dropwise over 2 hours. Water was added to the resultant reaction mixture, and white crystals formed were collected by filtration, washed with water and then recrystallized from methanol, thereby obtaining 12.3 g (yield: 74.6%) of the title compound (IIc-1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]2[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([O:16][CH3:15])[CH:18]=1
Reactant: COc1cccc(N)c1
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Product: COc1cccc(Nc2c(C#N)cnc3ccc(I)cc23)c1

Procedure:
Prepared from 1.00 g of 4-chloro-6-iodoquinoline-3-carbonitrile and 0.469 g of 3-methoxyaniline in the same manner as EXAMPLE 377. The crude product was filtered through silica gel with 20% EtOAc in CH2Cl2, evaporated and dried in vacuo (50° C.). The yield of 6-iodo-4-(3-methoxyphenylamino)quinoline-3-carbonitrile was 1.09 g as yellow crystals: mass spectrum (electrospray, m/e): M+H 401.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K+].[Br-]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CNCCN1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCNCC2)cc1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 4-methoxybenzenesulfonyl chloride (6.2 g, 30 mM) in CH2Cl2 (180 ml) is added to a solution of piperazine (12.9 g, 150 mM) in CH2Cl2 (570 ml) and pyridine (2.7 ml). The solution is maintained in agitation at room temperature for 15 h. The solvent is then removed under vacuum. The residue is dissolved in 3N HCl and washed with ethyl ether. The organic phase is removed and the aqueous phase is alkalized and extracted with ethyl acetate. The organic phase is dried over Na2SO4 and the solvent is removed under vacuum. A white solid is obtained (Yield=88%). P.f.: 184.3-185.6° C. FT-IR (KBr): 3082, 3058, 2975, 2944, 2907, 2840, 2810, 1597, 1580, 1495, 1465, 1442, 1413, 1346, 1318, 1298, 1286, 1254, 1179, 1159, 1110, 1095, 1066, 1027, 947, 830, 805, 734, 657, 634 cm−1. 1NMRs (300 MHz CDCl3, δ): 2.48-2.51 (m, 4H, two CH2 piperazine), 2.88-2.94 (m, 5H, two CH2 piperazine and NH), 3.86 (s, 3H, OCH3), 6.95-7.00 (m, 2H, aromatic protons), 7.64-7.68 (m, 2H, aromatic protons). 13C NMRs (75 MHz CDCl3, δ): 46.25, 50.57, 55.85, 77.82, 77.25, 77.67, 79.95, 114.40, 114.58, 127.32, 130.12, 163.27. GC-MS (70 eV) m/z (int. rel.): 258 [(34S)M+, 1], 256 [(32S)M+, 10], 171 (8), 108 (7), 92 (10), 85 (100), 77 (11), 64 (6), 63 (4), 56 (30). Anal. (C11H16N2O3S): Cal.: C, 51.54; H, 6.29; N, 10.93. Found: C, 51.59; H, 6.25; N, 10.96.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13](Br)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CN1CCCC1=O>O>[N:18]([C:13]([CH3:15])([CH3:14])[C:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:17])=[N+:19]=[N-:20]
Reactant: CC(C)(Br)C(=O)NCCOCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(N=[N+]=[N-])C(=O)NCCOCc1ccccc1
Temperature: 50 °C

Procedure:
A mixture of the crude amide (104 g), sodium azide (23.6 g) and N-methyl-2-pyrrolidone (500 ml) was heated at 50° C. for 22 h. After cooling to room temperatur water was added and the resulting mixture was extracted with diethyl ether (2×400 ml). The combined organic phases were washed with brine (3×500 ml) and dried (Na2 SO4). Evaporation of the solvents in vacuo gave 2-azido-N-(2-benzyloxyethyl)-2-methylpropionamide as an oil:78 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH2:36]([OH:38])[CH3:37]>>[CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:21][CH:20]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH3:37][C:36]([OH:17])=[O:38]
Reactant: CCO
Agent: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Product: CC(=O)O
Temperature: 60 °C

Procedure:
Bazedoxifene free base (1 g) and ethanol (10 mL) are mixed and heated to 60° C. to produce a clear solution, which is then filtered. The filtrate is cooled to 25-35° C. and acetic acid (4 mL) is slowly added at the same temperature. The mixture is cooled to 10-15° C., followed by addition of diisopropyl ether (5 mL) and seed crystals (20 mg, obtained from a previous example), and then additional diisopropyl ether (55 mL). The mixture is stirred for solid formation. The solid is collected by filtration and sequentially washed with diisopropyl ether (10 mL) and water (5 mL), then is suction dried for 5 minutes. The wet solid is dried under vacuum at 70° C. for about 4-5 hours to afford 900 mg (about 80% yield) of crystalline bazedoxifene acetate Form D.
Reaction SMILES: [CH2:1]([N:4]([CH:15]([CH2:35][CH:36]=C)[CH2:16][O:17][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=C>C(Cl)Cl.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[Si:18]([O:17][CH2:16][CH:15]1[CH2:35][CH:36]=[CH:2][CH2:1][N:4]1[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:6])=[O:7])([C:31]([CH3:32])([CH3:34])[CH3:33])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=CCC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CC=C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CC=CCC2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 132 %

Procedure:
To a solution of N-allyl-N-(1-((tert-butyldiphenylsilyl)oxy)pent-4-en-2-yl)-4-methylbenzenesulfonamide (D10) (7.12 g, 13.33 mmol) in DCM (64 ml), Grubb's catalyst (1.09 g, 1.32 mmol) was added and the mixture was stirred at RT overnight. After solvent evaporation, the residue was loaded on KP-Si (100 g) cartridge eluting with a mixture cHex/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D11) (8.9 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]([CH3:11])[O:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][C@@H:21]([CH3:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].CN1C(=O)CCC1>O.CCOC(C)=O>[CH3:25][C@@H:21]1[N:22]([C:2]2[C:3]3[CH:10]([CH3:11])[O:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:18])[CH2:20]1
Reactant: CC1OCc2ncnc(Cl)c21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1OCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 90 °C
Yield: 88.7 %

Procedure:
A mixture of 4-chloro-5-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (0.340 g, 1.99 mmol), (S)-tert-butyl-3-methylpiperazine-1-carboxylate (0.439, 2.19 mmol), TEA (0.56 mL, 4.0 mmol) and NMP (3 mL) was heat to 90° C. for 4 hours. The reaction was cooled to room temperature and diluted with H2O and EtOAc. The organic layer was separated and the aqueous layer extracted with EtOAc (3×20 mL). The combined organics were dried with MgSO4 and concentrated. The residue was purified by column chromatography (EtOAc) to give (3S)-tert-butyl 3-methyl-4-(5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.590 g, 89%) as an off white solid. LCMS (APCI+) m/z 235 [M-C5H9O2+H+]; Rt=2.71 min. This material was dissolved in DCM (5 mL) to which was added excess 4 N HCl in dioxane (2 mL) and the reaction allowed to stir at room temperature overnight. The reaction was concentrated to give 5-methyl-4-((S)-2-methylpiperazin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine dihydrochloride (0.540 g, 93%) was an off white solid. 1H NMR (CD3OD, 400 MHz) δ 8.82 (s, 1H), 5.83-5.79 (m, 1H), 5.18-5.05 (m, 1H), 4.48-4.36 (m, 1H), 3.87-3.73 (m, 1H), 3.58-3.52 (m, 1H), 3.48-3.43 (m, 3H), 1.51-1.46 (m, 5H). LCMS (APCI+) m/z 235 [M+H+]; Rt=1.13 min.
Reaction SMILES: Br[C:2]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[C:6]2=[O:14].C(OB([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:3]([C:23]1[CH:24]=[CH:25][C:26]([C:2]2[C:13]3[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([CH3:15])[C:6]3=[O:14])=[CH:27][CH:28]=1)([CH3:7])([CH3:4])[CH3:2]
Reactant: CC1Cc2c(cc3c(c2Br)CCC3)C1=O
Reactant: CC(C)(C)OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CC1Cc2c(cc3c(c2-c2ccc(C(C)(C)C)cc2)CCC3)C1=O
Yield: 139.6 %

Procedure:
0.3 g of palladium acetate (3 mol %) and 0.7 g of triphenylphosphine (6 mol %) were added to a well-stirred mixture of 12 g (0.045 mol) of 4-bromo-2-methyl-3,5,6,7-tetrahydro-s-indacen-1(2H)-one (1b), 11.2 g (0.063 mol) of tert-butylphenylboronic acid and 13.4 g (0.126 mol) of sodium carbonate in 170 ml of dimethoxyethane (DME)/56 ml of water. The reaction mixture was refluxed for 6 hours, poured into water and extracted with methylene chloride (5×100 ml). The combined organic phases were washed with sodium carbonate solution and water and dried over magnesium sulfate. After removal of the solvent, the crude product was chromatographed on silica gel (hexane/chloroform from 4/1 to 1/1). This gave 10 g (70% yield) of the compound (1c) as a viscous oil.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][C:22]([C:26]([F:27])([F:29])[F:28])=[CH:23][CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4cc(C(F)(F)F)ccc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4cc(C(F)(F)F)ccc43)nc12
Reaction time: 15 h
Yield: 7.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(trifluoromethyl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 207 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo, add 25 mL Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane, stir for 1 hour. concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(5-trifluoromethyl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (6 mg, 7%). MS (M−H)−=401; 1H NMR (DMSO-d6) δ: 9.04 (s, 1H), 8.74 (d, J=9.0 Hz, 1H), 8.54 (d, J=2.8 Hz, 1H), 8.46 (s, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 1.50 (s, 4H), 1.44 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:15][CH2:14][CH2:13][CH:12]2[C:16](OC)=[O:17])[O:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>C(OCC)C>[O:7]1[C:11]2([CH2:15][CH2:14][CH2:13][CH:12]2[CH2:16][OH:17])[O:10][CH2:9][CH2:8]1
Reactant: COC(=O)C1CCCC12OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCC1CCCC12OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a suspension of lithium aluminum hydride (630 mg, 16.6 mmol) in diethyl ether (30 ml), methyl 1,4-dioxaspiro[4.4]nonane-6-carboxylate (3.1 g, 16.6 mmol) obtained by the method of the step (80a) above was added at 0° C. The mixture was stirred at room temperature for 3 hours. Water (0.6 ml), a 5N aqueous sodium hydroxide solution (0.6 ml), and water (1.8 ml) were sequentially added at 0° C. to the mixture and the mixture was filtrated. After water was added to the filtrate and the organic layer was separated. The aqueous layer was extracted three times with ethyl acetate. The resultant extract was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (elution solvent: ethyl acetate/heptane=1/4, 1/1) to obtain the title compound (1.9 g, yield 72.4%) as a colorless oil.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][O-:5].[Na+].[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:12])[CH2:8][CH:9]=[CH:10][CH3:11]>C(O)CCC>[CH2:4]([O:5][CH:9]([CH2:10][CH3:11])[CH2:8][C:7]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:3][CH2:2][CH3:1]
Reactant: CC=CCC(=O)OCCCC
Reactant: CCCC[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(=O)CC(CC)OCCCC
Temperature: 65 °C
Reaction time: 6 h
Yield: 825.7 %

Procedure:
A solution of 4.8 g of sodium butylate in 74 g of n-butanol was added to 156 g of n-butyl 3-pentenoate at room temperature, and the mixture was heated to 65° C. and stirred at this temperature for 6 hours. The reaction mixture was cooled, n-butanol was distilled off, the residue was extracted by shaking with 25 ml of water, and the organic phase was dried over Na2SO4. Fractional distillation gave 95 g (41% of theory) of n-butyl 3-n-butoxyvalerate.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])([CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:28])[N:17]2[CH3:29])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:21]([N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])([CH3:30])[C:4]([OH:39])=[O:3])=[CH:8][CH:9]=2)[N:17]([CH3:29])[C:18]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccccc3)C(=O)N2C)cc1)Oc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)N(Cc2ccccc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is diluted with 1N HCl, extracted with CH2Cl2, dried, concentrated, and purified by LCMS to provide the title compound. 1H NMR (400 MHz, CDCl3): δ 7.55 (d, 1H, J=8.4 Hz), 7.34-7.21 (m, 6H), 7.10-7.01 (m, 4H), 6.74 (d, 2H, J=8.4 Hz), 4.46-3.36 (m, 2H), 3.96 (q, 2H, J=6.0 Hz), 3.74-3.65 (m, 1H), 3.45-3.39 (m, 1H), 3.28, 3.16 (ABq, 2H, J=14.7 Hz), 3.05 (q, 1H, J=8.6 Hz), 2.26-2.19 (m, 1H), 1.93-1.86 (m, 1H), 1.41 (s, 3H). MS [ES+] m/z exact mass calcd for C29H32N2O5F 507.2295, found 507.2308.