Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][S:7]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=[O:9])=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.O>[CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[S:7]([CH2:6][CH2:5][CH2:4][CH2:3][OH:2])(=[O:9])=[O:8]
Reactant: COC(=O)CCCS(=O)(=O)c1ccc2ccccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CCCCO)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
To a cooled (−78° C.) solution of the product of step b (1.00 g, 3.27 mmol) in THF (10 ml) was added dropwise a solution of lithium aluminium hydride (1M, THF, 3.50 ml, 3.50 mmol) and the mixture was stirred at this temperature for 3 h. The reaction mixture was treated sequentially with water (0.14 ml), aqueous sodium hydroxide (2M, 0.14 ml) and water (0.42 ml) and allowed to warm to ambient temperature. Sodium sulfate was added and the resultant suspension filtered through a pad of celite and the filter-cake washed with further ethyl acetate (150 ml). The filtrate was evaporated at reduced pressure and the residue purified by flash column chromatography (3:1 ethyl acetate:hexane) to afford the title compound (524 mg, 61%). 1H NMR 8.50 (1H, s), 8.04-7.86 (4H, m), 7.72-7.63 (2H, m), 3.66-3.62 (2H, m), 3.27-3.21 (2H, m), 1.91-1.83 (2H, m), 1.71-1.65 (2H, m), 1.56 (1H, br s).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:28]([CH3:44])[CH2:29][CH:30]=[C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:6]1)(=[O:3])[CH3:2].BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][C@H:17]([O:24][C:25](=[O:27])[CH3:26])[C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:28](=[CH2:44])[CH2:29][CH:30]=[C:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](OC(C)=O)[C@]2(C)[C@@H](C(C)CC=C(c4ccccc4)c4ccccc4)CC[C@@H]32)C1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3C[C@H](OC(C)=O)[C@]12C

Procedure:
A mixture of 3α, 12α-diacetoxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-5β-androstane (7.24 g), N-bromosuccinimide (2.26 g) and benzoyl peroxide (0.256 g) in anhydrous carbon tetrachloride (250 ml) is stirred at reflux, while being illuminated with a 275-watt sun lamp, for about 45 minutes. The mixture is cooled, filtered, and concentrated in vacuo. The resulting oil is dissolved in anhydrous pyridine (12.2 ml), the solution refluxed for about 1 hour, and concentrated in vacuo. The residue is dissolved in ether, filtered, and the ether solution washed with dilute sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is used, without further treatment, for the next step.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29])=[N:13][N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1.[Br:31]Br.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:31][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:8]=1[Cl:7])[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])[N:13]=[C:12]2[NH:25][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: BrBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
0.22 cm3 of pyridine is added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 25, in 15 cm3 of chloroform, followed by addition of 0.14 cm3 of bromine. The mixture is stirred for 24 hours at 20° C., followed by addition of 50 cm3 of dichloromethane and 50 cm3 of saturated aqueous sodium sulphate solution. After stirring for 10 minutes, the insoluble material is removed by filtration on a sinter funnel and the organic phase is washed with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60/m; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 940 mg of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide are obtained in the form of a white solid melting at 130° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=O)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:21][O:22][C:23](=[O:33])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH3:21][O:22][C:23](=[O:33])[CH2:24][N:25]([CH2:19][CH2:18][CH2:17][S:16][C:7]1[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:4])[CH3:3])[CH:6]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: COC(=O)CNCc1ccccc1
Solvent: CO
Product: COC(=O)CN(CCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Cc1ccccc1

Procedure:
Using the method of Example 39, the product from Example 38 was reacted with methanol and N-benzylglycine methyl ester to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH3:12])=[CH:16][CH:15]=1
Reactant: Brc1ccc(I)cc1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Product: COC(=O)c1ccc(-c2ccc(Br)cc2)c(C)c1
Yield: 23 %

Procedure:
In accordance with Example 19-(2), but using methyl 4-bromo-3-methylbenzoate instead of tert-Butyl 5-(benzyloxy)-2-{[1-(5-bromopyridin-2-yl)piperidin-4-yl]methyl}-6-methylpyrimidine-4-carboxylate, and 1-bromo-4-iodobenzene instead of tert-butyl[(4-iodobenzyl)oxy]dimethylsilane, the title compound (yield 23%) was afforded as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]([O:20]C(C)(C)C)=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N:15]([CH2:29][C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N(Cc2cccnc2)c2ccccc2C(=O)OC(C)(C)C)cc1OC1CCCC1
Solvent: O=CO
Product: COc1ccc(N(Cc2cccnc2)c2ccccc2C(=O)O)cc1OC1CCCC1
Temperature: 40 °C
Yield: 29.4 %

Procedure:
Tert-Butyl N-(3-cyclopentyloxy-4-methoxyphenyl)-N-(3-pyridylmethyl)-2-aminobenzoate (60 mg, 0.13 mmol) was taken up in 2 mL 98% formic acid and heated at 40° C. for 4 h. The formic acid was removed in vacuo and the residue was loaded onto a column of silica gel (RediSep, 4.2 g). The product was eluted with a linear gradient from 40% EtOAc in hexanes to 60% EtOAc in hexanes over 15 min to yield 16 mg of product as a brown solid. 1H NMR (CDCl3) δ 8.47 (d, 1H, J=4.9), 8.43 (s, 1H), 8.10 (d, 1H, J=7.8), 7.67 (d, 1H, J=7.8 Hz), 7.56 (m, 1H), 7.40–7.20 (m, 3H), 6.75 (d, 1H, J=8.7), 6.57 (d, 1H, J=8.7), 6.47 (s, 1H), 4.72 (s, 2H), 4.54 (p, 1H, J=4.3), 3.77 (s, 3H), 1.80–1.60 (m, 6H), 1.60–1.40 (m, 2H).
Reaction SMILES: C[Al](C)C.C([O:7][C:8]([C:10]1[C:11]2[N:12]=[CH:13][CH:14]=[N:15][C:16]=2[C:17]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)=[CH:18][CH:19]=1)=O)C.[CH2:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH2:45])=[N:43][CH:44]=2)[CH2:34][CH2:33]1)[CH3:31].O>C1(C)C=CC=CC=1>[CH2:30]([N:32]1[CH2:33][CH2:34][N:35]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([NH:45][C:8]([C:10]3[C:11]4[N:12]=[CH:13][CH:14]=[N:15][C:16]=4[C:17]([C:20]4[CH:21]=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=4)=[CH:18][CH:19]=3)=[O:7])=[N:43][CH:44]=2)[CH2:36][CH2:37]1)[CH3:31]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Trimethyl aluminum (2 M in toluene, 0.37 mL, 0.74 mmol, 2.5 equiv) was added to a mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) and 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by column chromatography) (78 mg, 0.36 mmol, 1.2 equiv) in toluene (2 mL). The reaction mixture was stirred for 1 h at rt, heated to reflux, stirred for 3 h, allowed to cool, poured onto EtOAc and H2O, and filtered through a pad of celite. The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by reverse-phase preparative HPLC to afford 54 mg of the title compound as a pale yellow solid. Title compound: ESI-MS: 513.2 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [BrH:1].[O:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[Br:1][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Br
Reactant: OCc1ccccc1Oc1ccccc1
Solvent: ClCCl
Product: BrCc1ccccc1Oc1ccccc1

Procedure:
Add 2-Phenoxy-benzoic acid (1 g, 4.67 mmol), in several portions, to a suspension of Lithium aluminium hydride (372 mg, 9.33 mmol) in dry THF (20 ml) at room temperature and stir. After 1 h, add aqueous 1M HCl dropwise carefully, then pour into H2O and extract three times with Et2O. Combine the organic phases, dry over Na2SO4 and concentrate at vacuum to yield pure (2-Phenoxy-phenyl)-methanol as courless oil. Add aqueous concentrated HBr (16 ml) to a solution of (2-Phenoxy-phenyl)-methanol (900 mg, 4.5 mmol) in CH2Cl2 (5 ml) and stir at room temperature. After 1 h. separate the organic phase and wash the aqueous one with CH2Cl2. Combine organic phases, wash with H2, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane:CH2Cl2, 2:1 to afford 1-Bromomethyl-2-phenoxy-benzene as colourless oil. 1H-NMR (CDCl3, 200 MHz): δ 7.44-7.01 (m, 8H), 6.84 (d, J=1.2 and 8.0 Hz, 1H), 4.60 (s, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]2[CH2:23][O:22]2)=[CH:17][CH:16]=1>C(O)C>[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:12][CH:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17][CH:16]=1
Reactant: CC(N)CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COc1ccc(OCC(O)CNC(C)CO[Si](C)(C)C(C)(C)C)cc1
Yield: 58.2 %

Procedure:
A procedure similar to that described in Preparation 10 was repeated, except that 3.22 g of 2-t-butyldimethylsilyloxy-1-methylethylamine, 3.00 g of 4-methoxyphenoxymethyloxirane and 30 ml of ethanol were used, to give 3.58 g of the title compound having an Rf value of 0.15 (on silica gel thin layer chromatography, using ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br)[CH3:2].C([Li])CCC.CON(C)[C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31]>C(OCC)C.CCCCCC>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:23]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[O:32])[CH3:2]
Reactant: CON(C)C(=O)c1ccc(Cl)cc1F
Reactant: CCOC(OCC)c1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(OCC)c1ccccc1C(=O)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 142.3 %

Procedure:
A stirred solution of 10.6 g of 2-bromobenzaldehyde diethyl acetal in 100 ml of diethyl ether was cooled to -40° C. To this cold solution was added rapidly 46 ml of a 1.2 M solution of butyllithium in hexane. The solution was warmed to 0° C. over 30 min. The solution was cooled down to -40° C. and a solution of 11.9 g of N-Methoxy-N-methyl-4-chloro-2-fluorobenzamide in 100 ml of diethyl ether added by cannular. The solution was warmed to 0° C. and stirred for 0.75 h then quenched by the addition of 100 ml of water and 200 ml of ether added. The organic layer was separated and the aqueous layer was extracted with 200 ml of ether. The combined organic layers were dried over sodium sulfate and evaporated to yield 19.6 g of crude [2-(diethoxymethyl)-phenyl](4-chloro-2-fluorophenyl)-methanone as a gum, GC-M.S. (E.I.) (M/Z) 336 [M]+.
Reaction SMILES: [C:1]1([OH:12])([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B:13](OC)(OC)[O:14][CH3:15]>>[CH3:15][O:14][B:13]1[O:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C:1]2([CH2:2][CH2:3][CH2:4][CH2:5]2)[O:12]1
Reactant: COB(OC)OC
Reactant: OC1(C2(O)CCCC2)CCCC1
Product: COB1OC2(CCCC2)C2(CCCC2)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
12-methoxy-11,13-dioxa-12-bora-dispiro[4.0.4.3]tridecane was prepared as follows. 5 g of bicyclopentyl-1,1′-diol was dissolved in 50 ml of trimethyl borate. The reaction mixture was stirred at room temperature under nitrogen for 2 days. Excess solvent was removed in a rotary evaporator and the residue was purified by vacuum distillation. Yield of the 12-methoxy-11,13-dioxa-12-bora-dispiro[4.0.4.3]tridecane was 5.27 g (85%) as a liguid with b.p. 68-70° C. 1H NMR (500 MHz, C6D6, TMS): δ 1.20-1.90 (m, 16 H, CH2), 3.20 (s, 3 H, MeO).
Reaction SMILES: O[N:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([OH:9])[CH:3]1O.[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(OC(=O)C)C>O1CCCC1.O>[OH:9][C:4]1[CH2:3][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: OC1=CC=C(O)N(O)C1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O)=CC=C1O
Reaction time: 5 h
Yield: 95.8 %

Procedure:
1 g (12 mmol) of 1,2,3,6-tetrahydroxypyridine and 2.76 g (12.6 mmol) of t-butyl dicarbonate was dissolved in 40 mL of tetrahydrofurane/water (1:1), and after stirring for 5 hour, 100 mL of ethylacetate was added thereto. After washing with water, an organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 2.1 g (11.5 mmol) of the title compound in a yield of 91%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]([CH3:19])[CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:33]1[C:41]2[C:36](=[C:37](B3OC(C)(C)C(C)(C)O3)[C:38]([F:42])=[CH:39][CH:40]=2)[CH:35]=[CH:34]1)(C(C)(C)C)(C)C>>[F:42][C:38]1[C:37]([C:2]2[N:3]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]([CH3:19])[CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:36]2[C:41](=[CH:40][CH:39]=1)[NH:33][CH:34]=[CH:35]2
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CN(Cc1ccc2nc(Cl)nc(N3CCOCC3)c2n1)CC(C)(C)O
Product: CN(Cc1ccc2nc(-c3c(F)ccc4[nH]ccc34)nc(N3CCOCC3)c2n1)CC(C)(C)O

Procedure:
1-(((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)(methyl)amino)-2-methylpropan-2-ol from Example 143 (0.12 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 35.6 mg of 140 following reverse phase HPLC purification. MS (Q1) 465.2 (M)+
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[F:14][C:11]([F:12])([F:13])[C:7]1[CH:6]=[C:5]([CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:31][CH:32]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1cccc(C(F)(F)F)c1
Yield: 35.8 %

Procedure:
Following a procedure similar to that described in Example 2, but using 5.88 g of 2-amino-1-(3-trifluoromethylphenyl)ethanol (prepared as described in Preparation 42), 8 g of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 2), 200 ml of benzene, 150 ml of absolute methanol and 5.4 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 4.8 g of the title compound were obtained as crystals, melting at 100°-105° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:25]/[C:26](/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:27]\[CH2:28][CH2:29][CH:30]=O>ClCCl>[Br:2][C:1]([Br:5])=[CH:30][CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:25])/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCC/C(C)=C/CCC=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCC/C(C)=C/CCC=C(Br)Br
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A dichloromethane solution (100 ml) of CBr4 (85 g, 256 mmols) was added dropwise to a stirred and ice-cooled dichloromethane solution (300 ml) of Ph3P (138 g, 526 mmols). To the mixture, a dichloromethane solution (100 ml) of the (E)-5-methyl-4-tetradecenal (5) (29.0 g, 129 mmols) was added while being cooled at 0° C. and stirred, followed by stirring the mixture for 15 minutes at 0° C. The reaction of this mixture was terminated by ice-cooled water (100 ml), and after 20 minutes of stirring, the organic layer was separated. The organic solution was dried (magnesium sulfate), and then concentrated in a vacuum. The residue was triturated with pentane (1 L), and insoluble Ph3PO was removed by filtration. The filtrate was concentrated in a vacuum, and then the oily residue was subjected to silica gel column chromatography, and eluted with n-hexane to obtain 38.1 g (77.6%) of oily (E)-1,1-dibromo-6-methyl-1,5-pentadecadiene (6).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14](OCC)[O:15]CC)=[CH:8][C:9]=1[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14]=[O:15])=[CH:8][C:9]=1[C:10]([CH3:11])([CH3:12])[CH3:13])=[O:4]
Reactant: CCOC(OCC)c1cc(C(C)(C)C)c(C(=O)OC)s1
Solvent: C1COCCO1
Solvent: O=CO
Product: COC(=O)c1sc(C=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
A solution of 5-diethoxymethyl-3-tert-butyl-thiophene-2-carboxylic acid methyl ester (1.84 g, 6.1 mmol) in dioxane (10 ml) was cooled to 0° C. (ice bath). 88% formic acid (20 ml) was added in one portion and the mixture was stirred at 0° C. for 5 min and then at rt for 2 h. The mixture was concentrated under reduced pressure to afford the desired product which was not further purified (1.57 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:23]([OH:25])=[O:24])=[CH:9][CH:8]=1
Reactant: O=C=O
Reactant: C#Cc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: -78 °C
Yield: 68 %

Procedure:
1.93 g (8.5 mmol) of 1-(3-fluoro-benzyloxy)-4-ethynyl-benzene is dissolved in 30 ml THF and cooled to −78° C. 5.8 ml (9.4 mmol) of a 1.6 molar solution of n-butyl lithium is slowly added under stirring. The resulting solution is stirred at −78° C. for 30 minutes. An excess of solid carbon dioxide is added and the suspension is slowly allowed to warm to RT. Water is added and the mixture is acidified by addition of aqueous 0.1 molar hydrochloric acid. Extraction with ethyl acetate yields a semi-solid residue which is triturated in diethyl ether to give 1.58 g (68%) of a colorless solid. MS (neg.ions): m/e=269.1 (M−H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Li+]>O1CCCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COC(=O)CCCc1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(CCCC(=O)O)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of methyl 4-(4-(N-(2,4-dimethylphenyl)-N-isobutylsulfamoyl)phenyl)butanoate (10.9 mg, 0.026 mmol) in tetrahydrofuran (THF) (0.25 mL) stirred in air at RT was added a solution of lithium hydroxide (0.625 mg, 0.026 mmol) in water (0.250 mL) in one charge. The reaction mixture was stirred at 20° C. for 30 min, to ensure dissolution and then left to stand overnight. Analysis showed complete conversion. The reaction mixture was evaporated and the residue partitioned between ethyl acetate 5 mL and water 5 mL, stirring vigorously for 2 hours before separation with a hydrophilic frit. Analysis showed product to be in both layers. Both layers were separately acidified (2N hydrochloric acid, ca. 1 mL), diluted with water (2 mL) and dichloromethane (2×3 mL). The organic fractions were separated by hydrophobic frit. The appropriate fractions were combined and dried under a stream of nitrogen in the Radleys blowdown apparatus to give the two batches of the required product 5.75 mg and 3.05 mg. LCMS (M+1) 404, RT 1.27 mins.