Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])(=[O:20])=[O:19].[CH3:22][S-:23].[Na+]>O1CCOCC1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:23][CH3:22])=[C:3]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:4]=2)=[O:17])=[CH:10][CH:11]=1
Reactant: C[S-]
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(SC)c(S(N)(=O)=O)c2)cc1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.15 g, 0.48 mmol) dissolved in dioxane (3 mL) is added sodium thiomethoxide (0.041 g, 0.57 mmol). The reaction mixture is heated at 90° C. for 4 h and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and methylene chloride, and the aqueous phase is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) gives 0.11 g (68%) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.4 (d, J=2 Hz, 1H), 7.90 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.00 (d, J=9 Hz, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 2.65 (s, 3H). Analytics calculated for C15H15NO4S2: C, 53.04; H, 4.48; N, 4.15. Found: C, 52.67; H, 4.57; N, 4.08. MS (m/z): 336 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)([CH3:7])[CH3:6])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1-c1ccccc1

Procedure:
2-(4-Benzyloxy-2-bromo-phenoxy)-2-methyl-propionic acid ethyl ester (3.00 g, 7.63 mmol) and phenyl boronic acid (1.12 g, 9.15 mmol) were dissolved in toluene (75 mL)/ethanol (75 mL). The solution was degassed (2×), and tetrakis(triphenylphosphine)palladium (70 mg, 0.061 mmol) was added followed by aqueous 2M Na2CO3 solution (7.63 mL, 15.3 mmol). The reaction mixture was degassed (2×) and heated to reflux under argon for 16 h. The reaction mixture cooled and partitioned between ethyl acetate (200 mL) and H2O (75 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated to a light brown oil (3.58 g). The crude product was used directly in the next reaction: 1H NMR (400 MHz, CDCl3) δ1.266 (t, 3H, J=7.1 Hz), 1.273 (s, 6H), 4.20 (q, 2H, J 7.1 Hz), 5.03 (s, 2H), 6.82 (dd, 1H, J=3.2, 9.0 Hz), 6.92 (d, 1H, J=8.8 Hz), 6.97 (d, 1H, J=3.0 Hz), 7.28-7.44 (m, 8H), 7.51-7.60 (m, 2H); MS (ES) m/e #[M+1].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([OH:33])[C:11]([O:29][CH2:30][O:31][CH3:32])([C:25]([F:28])([F:27])[F:26])[CH2:12][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])([CH3:15])[CH3:14])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10](=[O:33])[C:11]([O:29][CH2:30][O:31][CH3:32])([C:25]([F:26])([F:27])[F:28])[CH2:12][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])([CH3:15])[CH3:14])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COCOC(CC(C)(C)c1cc(F)ccc1OC)(C(O)Cc1cc(C)cc(C)c1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COCOC(CC(C)(C)c1cc(F)ccc1OC)(C(=O)Cc1cc(C)cc(C)c1)C(F)(F)F
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 137 mg (0.29 mmol) of 1-(3,5-dimethylphenyl)-5-(5-fluoro-2-methoxyphenyl)-3-methoxymethoxy-5-methyl-3-trifluoromethylhexan-2-ol (Example 12) in dichloromethane was added 350 mg (0.82 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane). After 1 hour, the reaction was quenched with saturated sodium bicarbonate, and filtered through diatomaceous earth, washing with EtOAc. The organic layer was separated and the basic aqueous phase extracted with two 5 mL portions of EtOAc. The combined organic layers were washed with 5 mL of saturated aqueous sodium bicarbonate, three 5 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified on a prep plate (2 mm, silica gel, EtOAc-hexanes (1:9), 3×developed) to afford 84 mg (61%) of 1-(3,5-dimethylphenyl)-5-(5-fluoro-2-methoxyphenyl)-3-methoxymethoxy-5-methyl-3-trifluoromethylhexan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:26])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[O:27]=[C:28]1[C@H:32]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:31][C:30](=[O:41])[O:29]1.C(O)(=O)C>C1C=CC=CC=1>[C:36]([O:35][C:34]([NH:33][C@@H:32]([C:28]([NH:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][CH2:19]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)=[O:27])[CH2:31][C:30]([OH:41])=[O:29])=[O:40])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(=O)OC1=O
Reactant: Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](CC(=O)O)C(=O)Nc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzenamine (206 mg, 0.570 mmol) and (R)-tert-butyl 2,5-dioxo-tetrahydrofuran-3-ylcarbamate (123 mg, 0.570 mmol) was added benzene (5.7 mL) and acetic acid (163 μl, 2.85 mmol) before it was stirred at 80° C. for 1 h. The two regioisomers were separated via SFC (Column: Princeton Pyridine, Mobile Phase: 60:40 liquid CO2/MeOH) to give (3R)-3-(tert-butoxycarbonylamino)-4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenylamino)-4-oxobutanoic acid and its regioisomer. MS (ESI) m/z: Calculated: 576.2; Observed: 577.1 (M++H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1.Cl.[OH:30][CH2:31][C@H:32]1[NH:36][CH2:35][C@H:34]([NH:37][C:38](=[O:40])[CH3:39])[CH2:33]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:7]=[C:6]([CH3:19])[C:5]=2[C:20]([N:22]2[CH2:27][CH2:26][CH:25]([N:36]3[C@H:32]([CH2:31][OH:30])[CH2:33][C@@H:34]([NH:37][C:38](=[O:40])[CH3:39])[CH2:35]3)[CH2:24][CH2:23]2)=[O:21])[CH2:3][CH2:2]1
Reactant: CC(=O)N[C@H]1CN[C@H](CO)C1
Reactant: Cc1nn(-c2cccc(C(F)(F)F)c2)c(C2CC2)c1C(=O)N1CCC(=O)CC1
Agent: Cl
Product: CC(=O)N[C@@H]1C[C@@H](CO)N(C2CCN(C(=O)c3c(C)nn(-c4cccc(C(F)(F)F)c4)c3C3CC3)CC2)C1

Procedure:
The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and N-((3R,5S)-5-hydroxymethyl-pyrrolidin-3-yl)-acetamide hydrochloride in direct analogy to the general procedure used in example 129. MS: 534.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[C:6](=[O:20])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8]=1[CH3:9])#[N:2].Cl.[NH2:36][OH:37].CC([O-])=O.[Na+].C(O)C>O>[CH3:34][S:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([C:5]2[C:6](=[O:20])[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)[C:8]([CH3:9])=[C:3]([C:1](=[NH:2])[NH:36][OH:37])[CH:4]=2)=[O:22])=[CH:30][CH:29]=1)(=[O:33])=[O:32]
Reactant: Cc1c(C#N)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=N)NO)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 28 %

Procedure:
5-Cyano-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (0.040 g, 0.082 mmol), hydroxylamine hydrochloride (0.015 g, 0.209 mmol), NaOAc (0.017 g, 0.209 mmol), ethanol (3 ml), water (0.1 ml) and a magnetic stirrer bar were placed in a vial. The mixture was heated (90° C.) overnight. LC-MS showed a 50:50 mixture of two components, one of which had the expected MW. The product was isolated by preparative HPLC giving 0.012 g (28%) of the intermediate N-hydroxyamidine.
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([Cl:17])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1oc(Br)nc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
To a solution of 2-bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-38) (1.30 g, 5.0 mmol) in CH2Cl2 (25 mL) was added oxalyl chloride (8.5 mL, 10.0 mmol) and DMF (0.019 mL), respectively, at RT under a nitrogen atmosphere. The reaction was stirred for 6 h at RT. The solvent was concentrated, and the residue was dried in vacuo to yield 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) as yellow oil (1.30 g, 96% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(C)C=CC=C[CH:10]=1.Cl[C:17]1[O:18][C:19]([C:26]([O-:28])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1>C(OCC)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:17]1[O:18][C:19]([C:26]([O:28][CH2:9][CH3:10])=[O:27])=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1
Reactant: CNc1ccccc1
Reactant: Cc1ccccc1
Reactant: O=C([O-])c1oc(Cl)nc1C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)c1oc(N(C)c2ccccc2)nc1C(F)(F)F

Procedure:
By the procedure of Example 15, 4.29 g (0.04 mol) of N-methyl aniline was added to 75 ml of toluene containing 4.87 g (0.02 mol) of 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate. The reaction mixture was stirred at reflux for 72 hours. The product mixture was slurried in ethyl ether, washed with water and 25% sulfuric acid, dried and concentrated. The residue was distilled and the distillate recrystallized from a chloroformmethylcyclohexane solution to yield 3.5 g of a white-powder product (m.p.=78°-81° C.) identified in Table I.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[C:10](Cl)(=[N:12][OH:13])[CH3:11].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:11][C:10]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=3)[O:13][N:12]=2)=[CH:26][CH:27]=1
Reactant: CC(Cl)=NO
Reactant: c1ccc(Oc2ccccn2)cc1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Oc3ccccn3)cc2)no1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 30.6 %

Procedure:
To a tetrahydrofuran (5 mL) solution of 3-ethynyl-pyridin-2-ylamine (45 mg, 0.38 mmol) described in Manufacturing Example 1-2-3 and (4-(pyridin-2-yloxy)benzene)-acetohydroximoyl chloride (200 mg, 0.76 mmol) described in Manufacturing Example 209-1-4 was added triethylamine (139 mg, 1.4 mmol), which was stirred for 10 minutes at 60° C. The reaction solution was cooled to room temperature, NH silica gel was added, and the solvent was evaporated under a reduced pressure. The crude product that had adsorbed to the NH silica gel was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1, 1:1) to obtain the title compound (40 mg, 30%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: O=CCCc1ccccc1Cl
Reactant: COC(=O)/C=C/C(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(c2ccccc2)OC(=O)[C@H]1Cc1ccccc1
Yield: 91 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxo-4-phenylbut-2-enoate using 0.5 mol % 1 as the catalyst in 91% yield as a 8:1 mixture of diastereomers (white solid). [α]D20 (c 1.16, CHCl3)=+130.4; mp=103-106° C.; 1H NMR (400 MHz, CDCl3) δ 7.67-7.61 (m, 2H), 7.41-7.27 (m, 6H), 7.27-7.17 (m, 2H), 5.82 (d, 1H, J=7.0 Hz), 5.75* (d, 1H, J=5.7 Hz), 3.77 (s, 3H), 3.69* (s, 3H), 3.61-3.58* (m, 1H), 3.56 (dd, 1H, J=14.3, 4.6 Hz), 3.42-3.37* (m, 1H), 3.32-3.28 (m, 1H), 3.17* (dd, 1H, J=13.8, 5.7 Hz), 3.04-2.99 (m, 1H), 2.92* (dd, 1H, J=13.8, 9.2 Hz), 2.77 (dd, 1H, J=14.3, 10.1 Hz); 13C NMR (100 MHz, CDCl3) δ 170.8, 168.9, 152.6, 138.2, 131.8, 129.8, 129.4, 129.2, 129.0, 128.8, 127.4, 127.1, 125.0, 98.1, 95.9, 52.9, 52.8, 42.8, 42.3, 41.2, 40.6, 35.5, 33.4; IR (thin film) ν 3061, 3028, 2952, 1777, 1733, 1496, 1448, 1173, 1069 cm−1; HRMS (ESI) calcd for C20H18O4 [M+Na]+ 345.1097, found 345.1094; >99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=32.4 min, tr (3R,4R)=20.3 min.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:18]2[C@H:25]3[C@H:21]([O:22]C(C)(C)[O:24]3)[C@@H:20]([CH2:28][OH:29])[O:19]2)=[O:7])=[CH:4][CH:3]=1.Cl[S:33]([NH2:36])(=[O:35])=[O:34]>>[S:33](=[O:35])(=[O:34])([O:29][CH2:28][C@@H:20]1[C@@H:21]([OH:22])[C@@H:25]([OH:24])[C@H:18]([N:13]2[CH:12]=[N:11][C:10]3[C:14]2=[N:15][CH:16]=[N:17][C:9]=3[NH:8][C:6](=[O:7])[C:5]2[CH:30]=[CH:31][C:2]([Br:1])=[CH:3][CH:4]=2)[O:19]1)[NH2:36]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(NC(=O)c3ccc(Br)cc3)ncnc21
Reactant: NS(=O)(=O)Cl
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccc(Br)cc4)ncnc32)[C@H](O)[C@@H]1O
Yield: 69 %

Procedure:
Using essentially the same procedure as example 39, step c, 4-bromo-N-{9-[(3aR,4R,6R,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}benzamide (0.305 g, 0.622 mmol) was reacted with chlorosulfonamide, and the product was purified by flash chromatography (50 to 100% EtOAc/hexanes) to afford the title compound (0.243 g, 69%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([NH:5][C@@H:6]1[C@H:12]([OH:13])[C@H:11]([CH3:14])[O:10][CH:8]([OH:9])[CH2:7]1)=[O:4].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]([NH:5][C@@H:6]1[C@:12]([S:18]([CH3:17])(=[O:20])=[O:19])([OH:13])[C@H:11]([CH3:14])[O:10][CH:8]([OH:9])[CH2:7]1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1OC(O)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(O)C[C@H](NC(=O)C(F)(F)F)[C@@]1(O)S(C)(=O)=O
Yield: 133.3 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy, 3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (504 mg, 1.41 mmol) in CH2Cl2 (7 ml) at 0° C. were added methanesulfonyl chloride (218 μl, 2.82 mmol) and triethylamine (590 μl, 4.2 mmol). After 2 hours the reaction mixture was worked up with CH2Cl2 and HCl 0.1N. The organic layer was washed with a solution of NaHCO3 and brine then dried over MgSO4. The solvent was evaporated to give 1-t-butyl dimethyl silyloxy, 3-trifluoroacetamido-2,3,6 trideoxy-4 methanesulfonyl-L-lyxohexopyranose (604 mg, 98%).
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[C:16]([N+:17]([O-])=[O:18])=[CH:15][C:14]([OH:20])=[C:13]([CH3:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].S(OC)(O[CH3:28])(=O)=O>O>[CH2:3]([O:10][C:11]1[C:16]([N:17]=[O:18])=[CH:15][C:14]([O:20][CH3:28])=[C:13]([CH3:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1cc(OCc2ccccc2)c([N+](=O)[O-])cc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(N=O)c(OCc2ccccc2)cc1C
Yield: 50 %

Procedure:
To 100 ml of methanol, there were added 24.6 g (95.0 mmol) of 4-benzyloxy-2-methyl-5-nitrophenol and 6.38 g (114 mmol) of potassium hydroxide and heated under reflux. To the obtained solution, there was added 14.4 g (114 mmol) of dimethyl sulfate and heated under reflux for additional one hour. After cooling and adding 200 ml of water, the crystals thus precipitated were filtered and recrystallized from hexane-acetone (2:1 (v:v)). Thus 13.0 g (47.5 mmol) of 4-benzyloxy-2-methyl-5-nitrosoanisole was obtained as yellow crystals. The yield was 50%.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])=[CH:51][CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)=[CH:51][CH:50]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccncc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccncc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 42.1 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-4-ylaniline (0.025 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 42% yield: LCMS (ESI) m/z 359 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:17]([F:18])=[C:16]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:24])=[C:12]([F:23])[C:13]=3[C:14]([F:22])([F:21])[C:15]2([F:20])[F:19])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:32]1([C:41](Br)([F:43])[F:42])[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:33]1>CN(C=O)C>[F:42][C:41]([F:43])([C:32]1[CH2:37][CH2:36][CH:35]([CH2:38][CH2:39][CH3:40])[CH2:34][CH:33]=1)[O:24][C:11]1[CH:10]=[CH:9][C:8]2[C:7]3[C:16](=[C:17]([F:18])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[C:15]([F:19])([F:20])[C:14]([F:21])([F:22])[C:13]=2[C:12]=1[F:23]
Reactant: CCCC1CCC(Br)(C(F)(F)Br)CC1
Reactant: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c-2ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1CC=C(C(F)(F)Oc2ccc3c(c2F)C(F)(F)C(F)(F)c2c-3ccc(OCC)c2F)CC1
Yield: 78.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of compound (91) (3.76 g, 10.80 mmol) and potassium carbonate (4.48 g, 32.4 mmol) was heated and agitated at 110° C. for 1 hour in a DMF (40 mL) solvent. Subsequently, 1-bromo-1-(bromodifluoromethyl)-4-propylcyclohexane (92) (7.21 g, 21.59 mmol) was added dropwise to the reaction mixture at 110° C., and the resultant mixture was further agitated for 3 hours. The reaction mixture was quenched with water, and extracted with 50 mL of toluene three times. Combined organic layers were washed with water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 2-(difluoro(4-propylcyclohexa-1-en-1-yl)methoxy)-7-ethoxy-1,8,9,9,10,10-hexafluoro-9,10-dihydrophenanthrene (93) (4.40 g, yield 78.0%) was obtained.
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:28]([C:31]1[CH:32]=[CH:33][C:34]2[O:40][CH2:39][C:38](=O)[CH:37]=[CH:36][C:35]=2[CH:42]=1)(=[O:30])[CH3:29]>O1CCCC1.CCCCC>[Cl:7][CH:8]=[C:38]1[CH:37]=[CH:36][C:35]2[CH:42]=[C:31]([C:28](=[O:30])[CH3:29])[CH:32]=[CH:33][C:34]=2[O:40][CH2:39]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc2c(c1)C=CC(=O)CO2
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
1.1 equivalents of n-butyllithium are added to 309 mg (0.89 mmol) of chloromethyltriphenylphosphonium chloride in 5 ml of tetrahydrofuran cooled to 0° C. After stirring for one hour, 150 mg (0.74 mmol) of 7-acetyl-1-benzoxepin-3(2H)-one, prepared according to example 79, are added at ambient temperature. The medium is stirred for a further 1 hour. After the usual treatments and evaporating the solvent under reduced pressure, the crude reaction product is taken up in pentane in order to precipitate triphenylphosphine oxide. Evaporation of the solvents provides 95.5 mg (55%) of 1-[3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]ethanone in the form of a mixture of two Z/E isomers in a 90/10 ratio; 1H NMR (C6D6): 7.85 (d, 1H, J=2.2 Hz), 7.76 (dd, 2.2 Hz and 8.4 Hz), 7.04 (d, 8.4 Hz), 6.85 (d, J-=11.8 Hz, 1H), 6.57 (d, J=11.8 Hz, 1H), 6.16 (s, 1H), 4.57 (4.87) (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25]O)=[N:21][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][N:21]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: Cc1ccc(OCCO)nc1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(F)ccc2n1CCOc1ccc(C)cn1

Procedure:
The ethyl 5-fluoro-1-[2-[(5-methylpyridin-2-yl)oxy]-ethyl]-1H-indole-2-carboxylate intermediate is prepared in a manner similar to the method described in Example 18.1, from ethyl 5-fluoro-1H-indole-2-carboxylate and 2-(5-methylpyridin-2-yloxy)ethanol prepared in the preceding step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[O:27][CH3:28].OS(O)(=O)=O.O>CN1C(=O)CCC1>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[N:3]=[C:4]([NH:17][CH3:18])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)=[CH:22][C:21]=1[O:27][CH3:28]
Reactant: COc1cc(N)ccc1Br
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1nc(Nc2ccc(Br)c(OC)c2)nc2c1CCC2c1ccccc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 2-chloro-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Ga) (0.24 g, 0.924 mmol), 4-bromo-3-methoxyaniline (0.187 g, 0.924 mmol) and H2SO4 (0.064 mL, 1.201 mmol) in NMP (Volume: 2 mL) was stirred in a sealed microwave tube at 90° C. overnight. The reaction was poured into 20 mL of water. The precipitate was collected by filtering. The cake was air dried. The cake was triturated with a minimum amount of cold MeOH to get 0.36 g (84%) of product as an off-white solid. LC-MS (M+H)+=425.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (1 H, br. s.), 7.68 (1 H, d, J=1.51 Hz), 7.53 (1 H, d, J=8.53 Hz), 7.34-7.42 (2 H, m), 7.24-7.34 (3 H, m), 6.94 (1 H, dd, J=8.66, 2.38 Hz), 4.36-4.51 (1 H, m), 3.83 (3 H, s), 3.05 (3 H, d, J=4.52 Hz), 2.79-2.95 (1 H, m), 2.59-2.77 (2 H, m), 1.93-2.12 (1 H, m).