Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])=[CH:14][CH:13]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 28.8 %

Procedure:
A solution of 15 (166 mg, 1.16 mmol) in dry THF (1.2 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-fluorophenylmagnesium bromide (1.3 equiv., 1.5 mmol, 1.9 mL, 0.8 M solution in THF). The reaction mixture was stirred at −78° C. for 3 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc (5 mL) was added to the reaction vessel and the organic layer was separated. The aqueous phase was extracted with EtOAc (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to afford 80 mg of 4h as a white solid: [α]22D +31.2° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.60-7.55 (m, 2H), δ 7.08-7.00 (m, 2H), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.17 (q, 1H, J=6.4 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.4 Hz); 13C NMR (CDCl3) δ 128.0, 127.9, 114.87, 114.58, 103.2, 98.4, 96.8, 69.5, 53.5, 27.3, 22.8, 16.4; LCMS (ESI) m/z 240.0 [(M+H)+, M=C13C18FNO2].
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][CH:8]=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:23][C:24](Cl)=[O:25].C1([N+]([O-])=O)C=CC=CC=1>C(Cl)Cl>[C:24]([C:8]1[CH:7]=[C:6]2[C:15](=[C:14]3[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:16]=[CH:17][C:18]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=1)(=[O:25])[CH3:23].[C:24]([C:12]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][CH:17]=[C:18]1[C:5]=3[CH:4]=[CH:3][CH:2]=[CH:1]1)(=[O:25])[CH3:23]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)ccc1c3ccccc3ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: CC(=O)c1cc2c3ccccc3ccc2c2ccccc12
Product: CC(=O)c1ccc2ccc3c4ccccc4ccc3c2c1

Procedure:
Friedel-Crafts reaction of chrysene with AlCl3 /CH3COCl/PhNO2 gave a mixture of 2-,3-, and 6-acetylchrysenes (285 g, Cambridge Chemical, Inc.). This was stirred and heated in CH2Cl2 (400 mL) and then filtered. The insoluble material, 2-acetylchrysene, was washed copiously with CH2Cl2. The solvent was removed from the filtrate. The resulting solid was dissolved in PhCH3, then the mixture containing the remaining two isomers chromatographed using PhCH3 as eluting solvent on a plug of SiO2 (1 kg). The faster eluting isomer is 6-acetylchrysene while the slower is 3-acetylchrysene. The chromatography gave 132 g of impure 6-acetylchrysene, and 76 g of impure 3-acetylchrysene. These materials were used without further purification. Pure samples of the compounds were obtained by preparative HPLC using PhCH3 as the eluting solvent.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[NH2:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Nc1c(Cl)cccc1CO
Product: Nc1c(Cl)cccc1COCc1ccccc1

Procedure:
This material was prepared from 2-amino-3-chlorobenzyl alcohol and benzyl bromide by the general procedure outlined in Example 98. The product was purified by Kugelrohr distillation to yield an oil, b.p. 118°-125° C. (0.1 mm). The product was characterized by IR and 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][C:12]=2[N:13]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[N:13]=1
Reactant: COc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2oc(-c3ccc(Cl)cc3Cl)nc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(2,4-dichlorophenyl)-5-methoxybenzoxazole (0.5 g, 1.7 mmol) was dissolved in 25 mL of dichloromethane. To the solution was added BBr3 (8 mmol) and the mixture was stirred at room temperature for 48 hours. The mixture was then diluted with 25 mL dichloromethane, and washed sequentially with saturated NaHCO3 (2×25 mL) and brine. The organic layer was separated, dried over MgSO4 and filtered. The solvent was removed, to provide 2-(2,4-dichlorophenyl)benzoxazol-5-ol, a compound of formula (g), which was purified using flash chromatography.
Reaction SMILES: II.[OH:3][CH2:4]/[CH:5]=[C:6](/[CH2:8][CH2:9]/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12])\[CH3:7].[CH2:19]([Sn:23]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]I)[CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:30]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][O:3][CH2:4][CH:5]=[C:6]([CH3:7])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: II
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 108.3 %

Procedure:
A 1.15 g (10.0 mmol) of 35% KH in mineral oil was washed with three 5 mL portions of dry hexane and suspended in 15 mL of dry tetrahydrofuran (THF) under argon. A solution of 242 mg (0.95 mmol) of iodine in 10 mL of THF was added over 50 minutes and the reaction was allowed to stir for an additional 40 minutes at room temperature to give a white suspension. (E,E)-Farnesol (1.5 g, 6.75 mmol) in 10 mL of THF was added dropwise over 15 minutes, and after 75 minutes, a solution of 2.43 g (5.64 mmol) of tributyl(iodomethyl)tin was added rapidly in 6 mL of THF. The mixture was stirred for three hours and carefully quenched with methanol. Upon dilution with diethyl ether, the organic layer was washed with water and brine, dried (MgSO4) and evaporated to give 3.21 g of a pale yellow liquid. The crude material was chromatographed on 720 g of silica gel eluted with 0.5:99.5 diethyl ether: petroleum ether, and the impure fractions were further purified on 150 g of silica gel eluted with 0.33:99.67 diethyl ether:petroleum ether to provide a total of 2.09 g (71%) of pure title stannane as a colorless liquid.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:21]([CH2:22][CH2:23][C@:5]12[CH3:6])[C@:18]1([CH2:19][OH:20])[C@H:13]([CH2:14][C@@H:15]([OH:24])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[C:27]1([Si:33]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:34][C@H:35]2[CH2:52][CH2:51][C@@:50]3([CH2:53][OH:54])[C@@H:37]([CH2:38][CH2:39][C@@H:40]4[C@@H:49]3[CH2:48][CH2:47][C@@:45]3([CH3:46])[C@H:41]4[CH2:42][CH2:43][CH:44]3[OH:55])[CH2:36]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C[Si](C)(C)OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CC[C@H]1C[C@@H](O)CC2>>[CH3:25][Si:2]([CH3:1])([CH3:26])[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:21]([CH2:22][CH2:23][C@:5]12[CH3:6])[C@:18]1([CH:19]=[O:20])[C@H:13]([CH2:14][C:15](=[O:24])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[C:56]1([Si:33]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:34][C@H:35]2[CH2:52][CH2:51][C@@:50]3([CH:53]=[O:54])[C@@H:37]([CH2:38][CH2:39][C@@H:40]4[C@@H:49]3[CH2:48][CH2:47][C@@:45]3([CH3:46])[C@H:41]4[CH2:42][CH2:43][C:44]3=[O:55])[CH2:36]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43CO)[C@@H]1CCC2O
Agent: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43C=O)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O[Si](c5ccccc5)(c5ccccc5)c5ccccc5)CC[C@@]43C=O)[C@@H]1CCC2=O

Procedure:
Substituting 17β-trimethylsiloxy-5α-androstane-3β,19-diol and 3β-triphenylsiloxy-5α-androstane-17,19-diol for the 19-trimethylsiloxy-5α-androstane-3β,17β-diol above results in the preparation of 17β-trimethylsiloxy-5α-androstane-3,19-dione and 3β-triphenylsiloxy-5α-androstane-17,19-dione.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH:38]1([CH2:41][NH2:42])[CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[CH:38]1([CH2:41][NH:42][CH2:2][C:3]2[N:7]([C:8]3[CH:9]=[C:10]([C:14]4[CH2:20][C:19](=[O:21])[NH:18][C:17]5[CH:22]=[C:23]([CH3:32])[C:24]([N:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:27])=[CH:25][C:16]=5[N:15]=4)[CH:11]=[CH:12][CH:13]=3)[N:6]=[N:5][CH:4]=2)[CH2:40][CH2:39]1
Reactant: NCC1CC1
Reactant: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CO)c1)CC(=O)N2
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc2c(cc1N(C)CC(C)C)N=C(c1cccc(-n3nncc3CNCC3CC3)c1)CC(=O)N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-8-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (250 mg, 0.58 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with cyclopropylmethylamine in DMF according to the method described in Example 45. Obtained as a light yellow solid (50 mg, 18%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[C:19]([CH3:25])[C:18]=2[OH:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH3:27][O:28]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:18]([OH:26])=[C:19]([CH3:25])[C:20]([CH3:24])=[C:21]([CH:27]=[O:28])[C:22]=2[CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c(O)c1C
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c(C=O)c(C)c(C(CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-(4-fluorophenyl)-7-(2-hydroxy-3,4,6-trimethylphenyl)heptanoic acid (7.5 g) and dichloromethyl methyl ether (5.7 ml) in dichloromethane (80 ml) was added a solution of titanium tetrachloride (6.9 ml) in dichloromethane (40 ml) over about 2 hours with ice-sodium chloride cooling. The reaction mixture was added to ice-water and the mixture was stirred for 30 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting crystals were recrystallized from acetonitrile to obtain 7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (7.8 g) (Compound 27). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[OH:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3cccc(O)c3)c2cc1OC
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 68, 4-chloro-6,7-dimethoxyquinazoline was reacted with 3-aminophenol to give 4-(3'-hydroxyanilino)-6,7-dimethoxyquinazoline in 92% yield, m.p. 256°-257° C. NMR Spectrum: 3.98 (s, 3H), 4.02 (s, 3H), 6.75 (m, 1H), 7.12 (d, 1H), 7.14 (d, 1H), 7.25 (t, 1H), 7.42 (s, 1H), 8.37 (s, 1H), 8.80 (s, 1H), 9.5 (broad hump, 1H), 11.4 (broad s, 1H); Elemental Analysis: Found C, 57.1; H, 4.8; N, 12.1; C16H15N3O3. 1HCl. 0.25H2O requires C, 56.8; H, 4.9; N, 12.4%.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.[NH4+].[Cl-]>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CCNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Reaction time: 18 h

Procedure:
4-nitrobenzyl chloride Compound 1n1 (4.0 g, 23.3 mmol) and pyrrolidine Compound 1n2 (4.8 mL, 58.3 mmol) were combined in THF (50 mL) at ambient temperature. After 18 hr, the reaction was diluted with 10% NH4Cl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to provide 1-(4-nitrobenzyl)-pyrrolidine Compound 1n3 (4.7 g) as a pale yellow oil without further purification (prepared as described in Mitsuru Shiraishi, et al., J. Med. Chem., 2000, 43, 2049-2063). 1H NMR (CDCl3) δ 8.17 (d, J=8.6 Hz, 2H); 7.51 (d, J=8.6 Hz, 2H); 3.72 (s, 2H); 2.58-2.48 (m, 4H); 1.89-1.72 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS(N=[C:29]=[O:30])(=O)=O.Cl.[OH-:32].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:29](=[O:30])[NH:15][C:14]2=[O:32])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
Combine 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carbonitrile (32 mmol) and dichloromethane (100 mL). Add chlorosulfonyl isocyanate (20 mmol) in dropwise fashion with water bath cooling so as to maintain the temperature of the reaction mixture between 20° and 30° C. After 30 minutes, concentrate the reaction mixture in vacuo to obtain a residue. Add 1N HCl (100 mL) and heat at reflux for 1 h. Cool in an ice bath and adjust the pH to 5.5 using 5N NaOH. Filter to obtain a residue. Wash with diethyl ether and dry in vacuo. Purify to obtain the title compound.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28].Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:28]([CH2:27][C:26]4[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=4[O:24][CH3:23])[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: COc1ccccc1CN
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccc1OC)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with o-methoxybenzylamine (0.18 mL, 1.4 mmol). Purification using silica gel, eluting with 5:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 103 as a white solid (m.p.205° C.).
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si:43]([C:56]([CH3:59])([CH3:58])[CH3:57])([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[CH:13]=[C:14]([F:15])[C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:29][CH2:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si:43]([C:56]([CH3:59])([CH3:57])[CH3:58])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH3:41])([CH3:34])[CH2:32][CH2:33]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3cc(F)cc(F)c3OCc3ccccc3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(CCCc3cc(F)cc(F)c3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Yield: 80.5 %

Procedure:
To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-3,5-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (190 mg, 0.190 mmol) in Ethanol (4 mL) was added 10% Pd—C (40.4 mg, 0.038 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vac to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(3,5-difluoro-2-hydroxyphenyl)propyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (140 mg, 0.153 mmol, 81% yield) as thick paste. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=7.3 Hz, 4H), 7.45-7.34 (m, 6H), 6.75-6.63 (m, 2H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.33-4.10 (m, 3H), 3.95-3.79 (m, 1H), 3.35 (br. s., 2H), 2.92-2.76 (m, 3H), 2.73 (br. s., 1H), 2.61 (s, 3H), 2.16-2.04 (m, 3H), 1.92 (br. s., 1H), 1.87 (br. s., 1H), 1.53-1.46 (m, 3H), 1.45-1.26 (m, 9H), 1.24 (s, 9H), 1.07 (s, 9H). LCMS (M+H)=913.9.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(Cl)Cl.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:31][CH:30]=2)[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(CBr)cc2)cc1
Reaction time: 12 h

Procedure:
A solution of 4-(bromomethyl)benzenesulfonyl chloride (5.6 mmol) in 5 mL of CH2Cl2 at 25° C. is treated with Et3 N (8.4 mmol) followed by bis-(4-methoxy-benzyl)-amine (5.8 mmol). The reaction is stirred for 12 hours, diluted with H2O, extracted with CH2Cl2, dried (MgSO4), filtered and concentrated. The resultant crude material is purified by silica flash chromatography (20% EtOAc/hexanes) to yield 4-bromomethyl-N,N-bis-(4-methoxy-benzyl)-benzenesulfonamide: 1H NMR (400 MHz, CDCl3): δ 7.72 (apparent t, J=8.4 Hz, 2H), 7.44 (dd, J1=1.6 Hz, J2=8.4 Hz, 2H), 6.91-6.86 (m, 4H), 6.69 (d, J=8.8 Hz, 4H), 4.5 (s, 2H), 4.19 (s, 4H), 3.71 (s, 3H); LC/MS: (ES+) 490.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=4[CH:34]=3)[CH2:19]2)=[N:14]1.ClC(Cl)C.[CH:39](=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[BH4-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:39]([N:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]2[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)[CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][N:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=4)[N:9]=[CH:8][CH:7]=3)[N:14]=2)[CH2:19]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N(Cc3ccccc3)Cc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.9 %

Procedure:
To a mixture of 6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one (30 mg, 0.06 mmol) and 4 Å molecular sieves (30 mg) was added dichloroethane (0.4 mL) and benzaldehyde (13 μL, 0.13 mmol). The solution was stirred for 1 h, after which NaB(OAc)3H (27 mg, 0.13 mmol) was added. After stirring overnight at RT, the reaction mixture was heated at 60° C. for 7 h. DMF (0.5 mL), NaBH4 (30 mg, 0.8 mmol) and CH2Cl2 (0.2 mL) were then added, and the reaction mixture was heated at 60° C. overnight. The mixture was diluted with satd. aq. NaHCO3 (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude was purified directly by basic reverse phase HPLC to afford 2 mg (5%) of the title compound. MS (ESI): exact mass calculated for C32H30N6O2S, 562.22; m/z found, 563.5 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7](O)[CH:8]([NH:22]C(OCC1C=CC=CC=1)=O)[CH2:9][CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2].C[OH:36]>>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH2:22])[CH:9]([OH:36])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)C(O)C(CCOc1c(F)c(F)cc(F)c1F)NC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)CC(N)C(O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Composition 13 (163 mg, 0.33 mmol) and MeOH (˜15 mL) was added to a dry round bottom flask equipped with a magnetic stir bar. The flask was purged several times with N2 and a catalytic amount of 10% Pd on C was carefully added to the reaction flask. The resulting black heterogeneous mixture was evacuated under vacuum and charged twice with H2 via a rubber balloon with constant stirring. The reaction was stirred at room temperature for 1.5 h and upon completion was filtered thru a pad of Celite, concentrated in vacuo to give 14 (115 mg, 0.32 mmol, 99% yield) as a sticky off-white solid. ESMS: 354.8 (M+H), 376.2 (M+Na+).