Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([C:28]2[O:29][C:25]([CH3:24])=[C:26]([CH2:42][CH2:43][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:14])([O:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=4)[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:27]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(OC(C)(Cc2ccc(OCCc3nc(-c4ccc(-c5ccccc5)cc4)oc3C)cc2)C(=O)O)cc1

Procedure:
A mixture 2-(p-tolyloxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester (0.030 mmol) (see Ex. 35, Part C), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-p-tolyloxy-propionic acid. 1H NMR (400 MHz, CDCl3) δ 8.87 (bs, 1H), 8.07 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=8.6 Hz), 7.65–7.63 (m, 2H), 7.50–7.38 (m, 3H), 7.19 (d, 2H, J=8.4 Hz), 7.04 (d, 2H, J=8.0 Hz), 6.82 (d, 2H, J=8.4 Hz), 6.80 (d, 2H, J=8.0 Hz), 4.23 (t, 2H, J=6.0 Hz), 3.24 and 3.22 (d of Abq, 2H, J=14.0 Hz), 3.09 (t, 2H, J=6.0 Hz), 2.45 (s, 3H), 2.28 (s, 3H), 1.38 (s, 3H). IR (KBr) 3450, 2924, 1719, 1682, 1509, 1207 cm−1. HRMS (ES+) m/z exact mass calcd for C35H34NO5 548.2437, found 548.2455.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:19])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(Br)cc2ccsc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc2ccsc12
Temperature: 0 °C
Yield: 51.1 %

Procedure:
The thiophene (10.16 g, 1.0 equiv), NBS (8.76 g, 1.1 equiv), and benzoyl peroxide (0.54 g, 0.05 equiv) were dissolved in CCl4, heated to reflux under UV irradiation for 2 hr and then cooled to 0° C. and filtered. The filtrate was evaporated. Repeated trituration with hexane gave 5-bromo-7-bromomethyl-benzo[b]thiophene (7.0 g). Concentration of the hexane gave an oil which was purified by column chromatography (SiO2, hexane) to give additional product (total yield 9.96 g, 86%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][CH2:29][O:30][CH2:31]Cl>C(#N)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: COCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
The mixture of 25.6 g (0.1 mol) of 7-benzyl-3-methylxanthine (prepared according to Example 1a), 15.2 g (0.11 mol) of potassium carbonate and 16.2 g (0.13 mol) of 2-methoxyethoxymethyl chloride in 500 ml of acetonitrile was heated at 50° C. with stirring for 5 hours, then worked up analogously to Example 1b) and the oily product obtained was purified by means of filtration on a silica gel column in the eluent chloroform/methanol (10/1).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[N:13][C:12]([OH:15])=[N:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CS(C)=O>[Cl:9][C:7]1[CH:6]=[C:5]([N:10]2[CH:14]=[N:13][C:12]([O:15][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:23])=[N:11]2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: Oc1ncn(-c2cc(Cl)cc(Cl)c2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
A 1.8 g portion of sodium was dissolved in 75 ml of absolute ethanol, and the solution was added slowly with stirring to a solution of 18.5 g of 1-(3,5-dichlorophenyl)-3-hydroxy-1,2,4-1H-triazole in 200 ml of dimethylsulfoxide. The solution was stirred at 60° for 1 hour, 14.5 g of ethyl 2-bromopropionate was added, and the mixture was heated for 2 hours at 100°-110°. It was then poured over ice water, and the solid was collected, dried and recrystallized from ether to obtain 10 g of the desired product. The mother liquor was chromatographed to obtain 1.3 g of additional product.
Reaction SMILES: [CH:1](=[C:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]2[NH:31][C:32](=[O:34])[O:33][C:29]=2[CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:1](=[C:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:26][C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(=Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(=Cc2ccccc2)CC1

Procedure:
A mixture of 49 mg (0.2 mmol) of (4-benzylidene-piperidine-1-yl)-oxo-acetic acid, 33 μl (0.24 mmol) of triethylamine, 30 mg (0.2 mmol) of 6-amino-3H-benzoxazol-2-one [J. Chem. Soc., 321. (1938)] 79.6 mg (0.21 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)]and 1 ml of dimethylformamide is stirred at room temperature for 24 h. The reaction mixture is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. The quality and the quantity of the product are determined by HPLC-MS method as described above. k′=9.66.
Reaction SMILES: [CH2:1]([Zn]CC)C.CCCCCC.FC(F)(F)C(O)=O.ICI.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@:29]([NH:51][S@:52]([C:54]([CH3:57])([CH3:56])[CH3:55])=[O:53])([C:37]2[CH:42]=[C:41]([O:43][C:44]([F:49])([F:48])[CH:45]([F:47])[F:46])[CH:40]=[C:39]([F:50])[CH:38]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[O:58][CH:59]=[CH2:60]>C(Cl)Cl>[CH:59]1([O:58][C:24]2[CH:25]=[C:26]([C@@:29]([NH:51][S@:52]([C:54]([CH3:56])([CH3:55])[CH3:57])=[O:53])([C:37]3[CH:42]=[C:41]([O:43][C:44]([F:48])([F:49])[CH:45]([F:46])[F:47])[CH:40]=[C:39]([F:50])[CH:38]=3)[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:23]=2[F:22])[CH2:1][CH2:60]1
Reactant: C=COc1cc([C@@](Cc2ccccc2)(N[S@@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reactant: CC[Zn]CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[S@](=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(OC2CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To an oven-dried 3-necked 25 mL RB flask under nitrogen was added CH2Cl2 (3.5 mL) and 1 M diethylzinc solution in hexane (3.43 mL, 3.43 mmol). The flask was cooled in an ice-bath and a solution of trifluoroacetic acid (0.391 g, 3.43 mmol) in CH2Cl2 (1 mL) was added dropwise via syringe. After stirring for 15 min, a solution of diiodomethane (0.918 g, 3.43 mmol) in CH2Cl2 (1 mL) was added. The reaction mixture was stirred at rt for 15 min, followed by addition of (S)—N—((R)-1-(4-fluoro-3-(vinyloxy)phenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.495 g, 0.87 mmol) in CH2Cl2 (1 mL). The reaction mixture was allowed to warm to rt and stirred for 4 h. The reaction mixture was diluted with CH2Cl2 and washed successively with sat. sodium bicarbonate, water, sat. NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO using a gradient of 5-70% EtOAc/hexane as eluent to yield (S)—N—((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a white foam (0.347 g, 71% yield). HPLC: RT=3.668 min [M+H] 586.3 (Phenomenex Luna C18 5μ column, eluting with 10-90% aqueous acetonitrile containing 0.1% trifluoroacetic acid over a 4 minute gradient, monitoring at 220 nm). 1H NMR (CDCl3) ppm 7.2-7.05 (m, 6H), 6.91 (d, J=6.6 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.71 (m, 2H), 5.84 (t, J=53.1 Hz, 1H), 4.21 (s, 1H), 3.99 (d, J=12.3 Hz, 1H), 3.62 (m, 1H), 3.56 (d, J=12.8 Hz, 1H), 1.22 (s, 9H), 0.72-0.65 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](Cl)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCl.[Cl-].[Na+].O>[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: c1ccc2c(c1)CCN2
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)N1CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.6 %

Procedure:
To a solution of indoline (2.0 g, 16.8 mmol) and triethylamine (5 mL) in dichloromethane (30 mL) was added slowly ethyl chlorooxalate (2.3 mL, 20.1 mmol) at 0° C. The mixture was stirred for 10 min at 0° C. and then for 1 h at room temperature. Brine was added and organic layer was separated. The organic layer was washed with diluted aqueous hydrochloric acid and successively brine, dried over magnesium sulfate, and concentrated to give 4.0 g of N-ethoxalylindoline (100%): 1H NMR (270 MHz, CDCl3) δ8.18 (dd, 1H, J=8, 1 Hz), 7.22 (m, 2H), 7.10 (dd, 1H, J=8, 1 Hz), 4.38 (q, 2H, J=7 Hz), 4.22 (t, 2H, J=8 Hz), 3.20 (t, 2H, J=8 Hz), 1.40 (t, 3H, J=7 Hz).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:66][C:64](=[O:65])[C@@H:62]([NH:63][C:19](=[O:21])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@@H:6]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:40])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])=[CH:31][CH:30]=1)=[O:14])[CH2:61][S:60][C:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2.50 g (4.42 mmol) of the compound from example 2A was dissolved in 100 ml dichloromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 20/1 and dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product.
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]#[N:24])[CH2:6]1)(=O)C.C[O-].[Na+].[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.O1CCCC1.C(OCC)(=O)C>[C:23]([C@@H:7]1[CH2:6][C@H:5]([S:4][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])#[N:24]
Reactant: CC(=O)S[C@H]1C[C@@H](C#N)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a suspension of (2S,4S)-4-acetylthio-2-cyano-1(-4-nitrobenzyloxycarbonyl)pyrrolidine (2.60 g) in a mixture of methanol (26 ml) and tetrahydrofuran (52 ml) was added a 28% solution of sodium methoxide in methanol (1.8 ml) at -10°~-5° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added trityl chloride (2.20 g) at -10°~-5° C., followed by stirring at the same temperature for 1 hour The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (40 g) and eluted with dichloromethane to give (2S,4S)-2-cyano-1-(4-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (2.45 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH:36]4[O:40][CH2:39][CH2:38][O:37]4)=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[ClH:42]>CO.O1CCOCC1>[ClH:42].[O:37]1[CH2:38][CH2:39][O:40][CH:36]1[CH2:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([CH2:22][O:21][C:17]3[CH:16]=[C:15]([CH:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH2:7])[CH:20]=[CH:19][CH:18]=3)[CH:24]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2cccc(-c3ccc(CC4OCCO4)cc3)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC(c1ccccc1)c1cccc(OCc2cccc(-c3ccc(CC4OCCO4)cc3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl((3-((4′-((1,3-dioxolan-2-yl)methyl)-[1,1′-biphenyl]-3-yl)methoxy)phenyl)(phenyl)methyl)carbamate (1.44 g, 2.6 mmol) in methanol (6.5 mL), was added hydrogen chloride in dioxan (6.5 mL). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated to afford a mixture of the title compound and the corresponding dimethyl acetal. The material was used in the next step without further purification.
Reaction SMILES: [NH:1]([C:8]1[C:18]([S:19](=[O:28])(=[O:27])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][C:9]=1[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[NH:1]([C:8]1[C:18]([S:19](=[O:28])(=[O:27])[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(=O)(=O)Nc2ccccc2)c1

Procedure:
Ethyl 4-anilino-3-benzylamino-5-phenylsulphamyl-benzoate (3 g) was dissolved in 1N sodium hydroxide (35 ml), and the solution was heated on a steam bath for 1 hour. After cooling, the reaction mixture was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid. The precipitated 4-anilino-3-benzylamino-5-phenylxulphamyl-benzoic acid was collected by suction and recrystallized from acetone/water. The compound was obtained with a melting point of 243°C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][C@H:21](O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:23]3[CH2:22][CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Temperature: 70 °C
Reaction time: 72 h
Yield: 41.1 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (4.0 g, 15.32 mmol, 1.0 eq), (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4.313 g, 21.44 mmol, 1.4 eq), and PPh3 (8.031 g, 30.64 mmol, 2.0 eq) in dry THF (200 mL), DIAD (4.658 g, 22.98 mmol, 1.5 eq) was added at room temperature. The reaction mixture was stirred at 70° C. for 72 h. The reaction mixture was concentrated and purified by silica gel chromatography (eluted with PE:EtOAc=1:1) to afford (R)-tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (2.8 g, 41.2% in yield).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C([Li])CCC.CCCCCC.[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[C:30](N(OC)C)=[O:31])[CH3:25]>C1COCC1.O.C(O)(C)C>[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([C:30]([C:2]2[CH:12]=[CH:11][C:5]3[N:6]([CH3:10])[CH2:7][CH2:8][O:9][C:4]=3[CH:3]=2)=[O:31])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH3:25]
Reactant: CCOc1cc(C(=O)N(C)OC)ccc1OC
Reactant: CN1CCOc2cc(Br)ccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CC(C)O
Product: CCOc1cc(C(=O)c2ccc3c(c2)OCCN3C)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
To a solution of 7-bromo-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 7.9 mmol) in THF (15 mL) was added a solution of n-butyllitium in hexane (2.6 mL, 2.5 N, 6.5 mmol) at −78° C. and kept for 10 min. To the mixture was added a solution of 3-ethoxy-4,N-dimethoxy-N-methyl-benzamide (1.4 g, 6.0 mmol) in THF (10 mL) at −78° C. After 30 min, isopropanol (2 mL) and water (30 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with water (50 mL), brine (50 mL) and dried over MgSO4. Removal of solvent and chromatography (Silica Gel) gave (3-ethoxy-4-methoxy-phenyl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-methanone as an oil (1.7 g, 87% yield): 1H NMR (CDCl3) δ 1.47 (t, J=7 Hz, 3H, CH3), 3.00 (s, 3H, CH3), 3.41 (t, J=4 Hz, 2H, CH2), 3.94 (s, 3H, CH3), 4.15 (q, J=7 Hz, 2H, CH2), 4.28 (t, J=5 Hz, 2H, CH2), 6.64 (d, J=8 Hz, 1H, Ar), 6.88 (d, J=8 Hz, 1H, Ar), 7.31-7.41 (m, 4H, Ar).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[F:24])=[N:3][CH:4]=1
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2,4-difluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.05–7.98 (3H, m), 7.44 (2H, d, J=8.6 Hz), 7.35–7.27 (1H, m), 7.06–6.93 (2H, m), 5.442–5.32 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 447 (M+H)+, 445 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[Br:12]N1C(=O)CCC1=O>ClCCl>[Br:12][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:11])[CH3:1])[C:7]#[N:8]
Reactant: CN(C)c1ccc(C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C)c1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
A mixture of 4-dimethylaminobenzonitrile (2.92 g, 20 mmol) and N-bromosuccinimide (3.56 g, 20 mmol) in dichloromethane (50 mL) was stirred at room temperature overnight. The solution was washed with water (20 mL), dried over magnesium sulfate and concentrated to afford 3-bromo-4-dimethylaminobenzonitrile as a white solid (4.27 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[CH:12]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]2
Reactant: COc1cc(F)c(-c2ccc3cc(OC)ccc3c2)c(F)c1
Agent: BrB(Br)Br
Product: Oc1cc(F)c(-c2ccc3cc(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by reacting 2-(2,6-difluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.5 g, 5.0 mmol) with boron tribromide (25 mL of 1.0 M solution in CH2Cl2, 25 mmol) according to method D to yield 1.35 g (99%) of a yellowish solid: mp>240° C.; 1H NMR (DMSO-d6): δ 6.55–6.63 (2H, m), 7.11 (1H, dd, J=8.76 Hz, J=2.34 Hz), 7.15 (1 h, d, J=2.05 Hz), 7.36 (1H, dd, J=8.58 Hz, J=1.34 Hz), 7.39 (1H, d, J=8.83 Hz), 7.79 (1H, s), 7.80 (1H, d, J=8.74 Hz), 9.85 (1H, s), 10.48 (1H, s); MS (ESI) m/z 271 (M−H)−; MS (ESI) m/z 543 (2M−H)−.