Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C=O)C.[NH2:11][C:12]1[S:13][C:14]2[C:19](O)=[N:18][C:17]([S:21][C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH3:23])=[N:16][C:15]=2[N:31]=1.O>O1CCOCC1>[Cl:3][C:19]1[C:14]2[S:13][C:12]([NH2:11])=[N:31][C:15]=2[N:16]=[C:17]([S:21][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH3:23])[N:18]=1
Reactant: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(Cl)c2sc(N)nc2n1)c1ccccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
POCl3 (2.77 mL, 29.7 mmol) was added to DMF (3.07 mL, 39.6 mmol) in dioxane (30 mL). After 30 minutes this mixture was added to a solution of 2-amino-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-ol (6.38 g, 19.8 mmol) in dioxane (100 mL). After 30 minutes POCl3 (2.77 mL, 29.7 mmol) was added, the reaction mixture was heated to 80° C. for 2 h. After cooling to room temperature, water (20 mL) was carefully added and the resulting mixture was stirred at 80° C. for 30 minutes and at room temperature for 2 h. The reaction mixture was poured into water and the formed precipitate was collected. The solid was purified by flash column chromatography (5% MeOH in CHCl3) to give the title compound (5.91 g, 88% yield).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:27]=[C:18]3[C:19]4[C:24]([CH2:25][CH2:26][N:17]3[N:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:27]=[C:18]3[C:19]4[C:24]([CH2:25][CH2:26][N:17]3[N:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(COc2cccc(-c3nc4n(n3)CCc3ccccc3-4)c2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1cccc(-c2nc3n(n2)CCc2ccccc2-3)c1

Procedure:
2-(3-Benzyloxyphenyl)-5,6-dihydro-s-triazolo-[5,1-a]isoquinoline (17.7 g.) is dissolved in 500 ml. of ethanol and hydrogenated at atmospheric pressure and room temperature in the presence of 3 g. of 10% Pd on charcoal. After filtration of the catalyst, the solution is concentrated to 100 ml. The product which precipitates on cooling is purified by crystallization from ethanol. Yield 10.1 g.; m.p. 201°-2° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)[CH3:2].[OH-].[Na+]>CC(C)=O.C(O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:15]=[C:14]([CH2:16][OH:17])[CH:13]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Yield: 42.8 %

Procedure:
Add a solution of diethyl-5-(hydroxymethyl)-isophthalate (5 g, 19.8 mmol) in acetone (88 mL) to a solution of NaOH (792 mg, 19.8 mmol) in ethanol (12 mL). After 4 h collect precipitate. Dissolve the precipitate in water (200 mL), add 5 N HCl to about pH=1 and collect the precipitate. Extract the aqueous with dichloromethane, combine the extracts with the precipitate and concentrate to give to give the title compound (1.9 g, 43%)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:34])[C:25]([CH2:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])[CH:10]=3.C(=O)([O-])O.[Na+]>C(O)(=O)C.Br>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:24](=[O:34])[C:25]([CH2:27][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)=[CH:26][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=3
Reactant: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c(c1)c23
Yield: 78.7 %

Procedure:
9-bromo-2-t-butoxycarbonylmethyloxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (57 mg) produced in Example 103 was dissolved in acetic acid (0.5 ml) and 48% HBr (0.5 ml), and the solution was stirred at 60° C. for 1 hour and allowed to cool. Saturated aqueous solution of sodium hydrogencarbonate was added to pH 7, and the crystals precipitated were recovered by filtration, washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (40 mg, 79%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]1C=CC=C(N)C=1>>[CH3:13][C:12]1[C:7]([NH:6][C:1]2[CH:2]=[N:23][CH:3]=[CH:4][CH:5]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1cccnc1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccnc2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using pyridin-3-amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.11 (s, 3H), 2.35 (s, 3H), 4.71 (d, J=3.0 Hz, 2H), 5.97 (bs, 1H), 6.41 (bs, 1H), 7.13-7.20 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 8.05 (d, J=4.0 Hz, 1H), 8.26 (bs, 1H), 8.56-8.63 (m, 2H); MS (ESI) m/z 307.9 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([O:19][CH3:20])[C:16]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([C:22]#[N:21])=[CH:24][CH:25]=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C(=O)O)c1cccc(OCc2ccccc2)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(OCc2ccccc2)c1

Procedure:
(RS)-(3-Benzyloxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(3-benzyloxy-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[C:23]([OH:25])=O)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:29])=O>CN(C=O)C.C(Cl)Cl>[Cl:29][C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])=[O:25]
Reactant: O=C(O)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a solution of 1-(((9H-fluoren-9-yl)methoxy)carbonyl)pyrrolidine-2-carboxylic acid (1.2 mg, 3.6 mmol) and 2 drops DMF in DCM was added oxalyl dichloride (2 g, 15.9 mmol), resulting in bubbling of the solution. After the solution stopped bubbling, the reaction solution was concentrated to give the crude product, which was directly used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1>[Pd].CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:6]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:14][CH:15]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(CCc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Into the reaction flask was added tert-butyl [5-({5-amino-2-[(tert-butoxycarbonyl)amino]phenyl}ethynyl)pyridin-3-yl]carbamate (1.5 g, 3.5 mmol) and methanol (30 mL) and 10% palladium on carbon (0.15 g, 0.14 mmol). The reaction mixture was hydrogenated at 25 psi for 2 h. The mixture was filtered and concentrated to give the desired product (1.4 g, 92%). LCMS for C23H33N4O4 (M+H)+: m/z=429.1.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:19]2[S:23][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:20]=2[CH3:34])[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH3:35])[CH3:6])C.[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH3:6][C:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:19]2[S:23][C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)=[N:21][C:20]=2[CH3:34])[CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH3:35])([CH3:36])[C:4]([OH:37])=[O:3]
Reactant: CCCC(Oc1ccc(OC(C)(C)C(=O)OCC)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(Oc1ccc(OC(C)(C)C(=O)O)c(C)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a solution of example 34 (800 mg, 1.5 mmol) in THF/Ethanol (5/20 mL) was added 1N NaOH (10 mmol, 10 mL). The resulting mixture was stirred at 50° C. for 2 hours, and after cooling at room temperature 1N HCl (10 mmol, 10 mL) was added. The resulting mixture was concentrated in vacuo, then the residue was flash chromatographed CH2Cl2/MeOH (98:2) to give the title compound (310 mg, 0.61 mmol) in a 40% yield as a colorless oil.
Reaction SMILES: [Mg].Br[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[C:18]([CH:33]=[O:34])=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:21][CH:22]=1.[Cl-].[NH4+]>C(OCC)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][C:18]=1[CH:33]([OH:34])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Reactant: CC(C)(C)CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CC(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of magnesium (133 mg) and diethyl ether (10 mL) was added 1-bromo-2,2-dimethylpropane (0.68 mL), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (1.02 g) in diethyl ether (5 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (674 mg) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:10]([O:12]C)=[O:11])[NH:8][CH:9]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[NH:8][CH:9]=1
Reactant: COC(=O)c1cc(Cc2c(F)cc(F)cc2F)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cc2c(F)cc(F)cc2F)c[nH]1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100.6 %

Procedure:
To a methanol 30 mL solution of methyl 4-(2,4,6-trifluorobenzyl)-1H-pyrrole-2-carboxylate (840 mg, 3.1 mmol) was added 5N sodium hydroxide solution (3.1 mL, 16 mmol) and the reaction was stirred in an oil bath at 70° C. overnight. After cooling to rt, pH of the reaction mixture was adjusted to 1.5 to give a gray suspension. The precipitate was collected by suction filtration and dried under vacuum to give the title compound (796 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][NH:17][CH2:18]2)=[CH:13][CH:12]=1)=[O:10].[C:21]1([CH2:27][CH2:28][N:29]=[C:30]=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[C:21]1([CH2:27][CH2:28][NH:29][C:30]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])=[CH:12][CH:13]=3)[CH2:18]2)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CNCC2
Reactant: O=C=NCCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)NCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 200 mg N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide, 117 mg phenylethyl-isocyanat, 98 mg HOBt, 278 mg EDC, 0.6 ml triethylamine and 8 ml DMF is stirred overnight at ambient temperature. The mixture is evaporated. The residue is purified by silica gel flash chromatography. 208 mg of the title compound are obtained after drying as colorless foam.
Reaction SMILES: C(OC1C=C(C=CC=1O)C[N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C.Cl.Cl.COC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH:61]=O)=[CH:59][C:58]=1[O:65][CH2:66][CH2:67][CH3:68]>>[CH3:55][O:56][C:57]1[CH:64]=[CH:63][C:60]([CH2:61][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:59][C:58]=1[O:65][CH2:66][CH2:67][CH3:68]
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Reactant: CCCOc1cc(C=O)ccc1OC
Agent: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Agent: Cl
Product: CCCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1OC

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid (example 201) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 4-methoxy-3-propoxy-benzaldehyde (intermediate E11) in a yield of 16.4 mg (23%). MS (ISP): 468.3 [M+H]+.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH2:13]([O:20][C@@H:21]1[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:24][C:22]1=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCCCC.O1CCCC1>[CH2:13]([O:20][C@@H:21]1[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:25]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:24][C:22]1([OH:23])[CH2:6][P:7]([O:10][CH3:11])([O:8][CH3:9])=[O:12])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COP(C)(=O)OC
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
A solution of n-butyllithium in n-hexane (1.6M solution, 68.8 ml) was added to a solution of dimethyl methylphosphonate (13.65 g) in tetrahydrofuran (200 ml) in a stream of argon at -70° to -78° C., and then stirred for 30 min. To the solution was added a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (29.6 g) in tetrahydrofuran (150 ml) at -70° to -78° C. The mixture was stirred for 1 hour at the same temperature. The cooling bath was removed and the mixture was allowed to warm to 0° C. with stirring. Ice-cold 10% ammonium chloride solution (400 ml) was added to the reaction mixture and the resulting oily substances were extracted with ethyl acetate (1.2 l). The ethyl acetate solution was washed with 2N hydrochloric acid and saturated aqueous sodium hydrogen-carbonate, dried with anhydrous sodium sulfate and then evaporated in vacuo. Ethyl ether-petroleum ether (1:3; 400 ml) was added to the residue and the mixture was refrigerated to give 3,4,5,7-tetra-O-benzyl-1-deoxy-1-(dimethoxyphosphoryl)-D-gluco-2-heptulopyranose (33.1 g) as white crystals; m.p. 112°-113° C.;
Reaction SMILES: [C:1]1([CH2:7][S:8](F)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O-:14].[K+:17]>O1CCCC1>[C:1]1([CH2:7][S:8]([O-:10])(=[O:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:17]
Reactant: C[Si](C)(C)[O-]
Reactant: O=S(=O)(F)Cc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])Cc1ccccc1
Yield: 58.3 %

Procedure:
The procedure of Example 1 was followed using α-toluenesulfonyl fluoride (2.0 g, 11.5 mmol) in dry tetrahydrofuran (15 mL), potassium trimethylsilanolate (1.48 g, 11.5 mmol) and dry tetrahydrofuran (45 mL), and 2 h of heating at reflux. Potassium α-toluenesulfonate (1.41 g, 58% yield) was isolated as a white solid: 1H NMR (D2O) δ 4.1 (s, CH2, 2H), 7.4 ppm (s, Ar--H's, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.[Na].C(O)CC(C)C.C(OCC)C>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6]2
Reactant: COC(=O)C(C)c1ccc2cc(OC)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CC(C)CCO
Product: COC(=O)C(C)C1=Cc2ccc(OC)cc2CC1

Procedure:
A mixture of 24.4 g. of methyl 6-methoxy-2-naphthyl-α-methylacetate, 25 g. of sodium metal, and 500 ml. of anhydrous iso-amyl alcohol are refluxed for 18 hours. The cooled reaction mixture is acidified by the addition of aqueous IN hydrochloric acid. The product is isolated by diethyl ether extraction to give methyl 6-methoxy-3,4-dihydro-2-naphthyl-α-methylacetate.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][C:14]2([CH3:23])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)C.ClCCl>[Br:10][C:11]1[CH:12]=[C:13]2[C:18]([C:17]([C:4]3[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=3)=[CH:16][CH2:15][C:14]2([CH3:23])[CH3:22])=[CH:19][CH:20]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
p-Tolyl magnesium bromide (1 M solution in diethyl ether, 4.2 mL, 4.17 mmol) was added slowly to a solution of 6-bromo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 3, 350 mg, 1.39 mmol) in 10 mL of diethyl ether at 0° C. After stirring and warming to room temperature for 2 h, the mixture was quenched with water at 0° C., extracted with diethyl ether (3×5 mL), washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure to give a light yellow oil. The crude oil was then dissolved in 10 mL of dichloromethane and stirred with 100 mg of para-toluenesulfonic acid at room temperature for 2 h. Water (10 mL) was then added and the organic layer was washed with brine (1×5 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (hexane) gave the title compound (295 mg, 65% yield) as a colorless oil:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[O:9][C:10](=[O:11])[C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:20].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[N:7]([CH3:20])[C:8](=[O:12])[O:9][C:10](=[O:11])[C:5]=2[CH:4]=1
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
9.00 g (40.3 mmol) 6,7-Dimethoxy-1H-benzo(d)(1,3)oxazine-2,4-dione were dissolved in 60 ml dried dimethylformamide and cooled to 0° C. 1.32 g (52.3 mmol) sodium hydride was added and the solution was stirred for 30 min at room temperature (Argon). After cooling to 0° C. again 7.42 g (3.27 ml, 52.3 mmol) iodomethane was added and stirred at room temperature for 1 h. 300 ml water was added and the residue is filtrated, rinsed with water and ethyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:36].[CH2:37]([OH:40])[CH:38]=[CH2:39].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CS(C)=O.F[B-](F)(F)F.C([N+]1C=CN(C)C=1)CCC.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:36][C:3]1[CH:4]=[C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:7][C:2]=1[C:38]([CH2:37][OH:40])=[CH2:39]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[n+]1ccn(C)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=C(CO)c1ccc(N(c2cc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc2C2CC2)S(C)(=O)=O)cc1Cl
Temperature: 135 °C
Yield: 23.9 %

Procedure:
A mixture of 6-(N-(4-bromo-3-chlorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (327 mg, 0.552 mmol), allyl alcohol (0.475 mL, 6.9 mmol), palladium(II) acetate (29 mg, 0.132 mmol), 1,3-bis(diphenylphosphino)propane (108 mg, 0.26 mmol) and triethylamine (0.7 mL, 4.9 mmol) in DMSO (2 mL) and 1-butyl-3-methylimidazolium tetrafluoroborate (2 mL) was heated at 135° C. in a sealed tube for 59 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. Chromatography on silica gel (hexane:ethyl acetate) gave 75 mg (24%) of 6-(N-(3-chloro-4-(3-hydroxyprop-1-en-2-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide. 1H NMR (400 MHz, chloroform-d) δ ppm 7.84-7.97 (m, 2H) 7.60 (s, 1H) 7.48 (s, 1H) 7.37-7.41 (m, 1H) 7.29-7.32 (m, 1H) 7.28 (s, 1H) 7.16-7.24 (m, 3H) 5.77-5.97 (m, 1H) 5.51-5.63 (m, 1H) 5.17 (s, 1H) 4.34-4.46 (m, 2H) 3.28 (s, 3H) 3.00 (d, J=4.88 Hz, 3H) 2.1 (m, 1H) 0.99-1.10 (m, 1H) 0.77-0.93 (m, 2H) 0.48-0.73 (m, 1H).). LCMS (m/z, ES+)=569 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[C:17](=[O:26])[NH:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=2)[CH:5]=1.O.[OH-].[Na+]>C1COCC1>[CH3:25][C:21]1[CH:20]=[C:19]([NH:18][C:17]([C:12]2[N:13]=[C:14]([CH3:16])[S:15][C:11]=2[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=2)=[O:26])[CH:24]=[CH:23][N:22]=1
Reactant: COC(=O)c1cccc(Nc2sc(C)nc2C(=O)Nc2ccnc(C)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cccc(CO)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
3-[2-Methyl-4-(2-methyl-pyridin-4-ylcarbamoyl)-thiazol-5-ylamino]-benzoic acid methyl ester (example 222, 0.425 g, 1.11 mmol) was dissolved in 15 mL dry THF. Lithiumalumiumhydride (0.169 g, 4.44 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. Water (0.169 mL), 15% NaOH (0.169 mL) and again water (0.507 mL) was slowly added and the reaction mixture was filtered and evaporated. The crude material was recrystallized from ethyl acetate and dichloromethane to yield the title compound as a yellow solid (0.257 g, 65%), MS (ISP): m/e=355.3 (M+H+).