Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:12][P:13]([CH3:16])(=[O:15])[OH:14])[CH:6]=[CH:5][C:4]([CH2:7][P:8]([CH3:11])(=O)[OH:9])=[CH:3][CH:2]=1.C(Cl)(Cl)=O>>[C:1]12[CH2:12][P:13]([CH3:16])(=[O:15])[O:14][P:8]([CH3:11])(=[O:9])[CH2:7][C:4]([CH:5]=[CH:6]1)=[CH:3][CH:2]=2
Reactant: CP(=O)(O)Cc1ccc(CP(C)(=O)O)cc1
Agent: O=C(Cl)Cl
Product: CP1(=O)Cc2ccc(cc2)CP(C)(=O)O1
Yield: 100 %

Procedure:
44 Grams of p-xylylene-bis-(methylphosphinic acid) are heated to 240° C., and phosgene is slowly introduced, while stirring. In the course of 1.5 hours the temperature is reduced to 210° C. Subsequently nitrogen is passed through the mixture at this temperature. 41 Grams of p-xylylene-bis-(methylphosphinic acid)-anhydride are obtained which have a solidification point of from about 165° to 175° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH2:7][C:8]#[N:9].[N:14]([Sn](CCCC)(CCCC)CCCC)=[N+:15]=[N-:16].C([Al](CC)CC)C>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH2:7][C:8]1[NH:16][N:15]=[N:14][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CNc1ccccc1OCCC#N
Agent: CC[Al](CC)CC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CNc1ccccc1OCCc1nnn[nH]1
Temperature: 80 °C

Procedure:
To a solution of 3-(2-methylamino-phenoxy)-propionitrile (1.55 g, 8.8 mmol) and azidotributyltin (3.6 mL, 13.2 mmol) in toluene (30 mL) was added triethylaluminum (9.3 mL, 17.6 mmol, 1.9 M in toluene). The mixture was heated at 80° C. for 16 hrs. The mixture was diluted with water (100 mL) and ethyl acetate (200 mL). The ethyl acetate layer was separated and removed. The resulting methyl-{2-[2-(1H-tetrazol-5-yl)-ethoxy]-phenyl}-amine stayed in the aqueous solution and was used in the next step without purification. [M+H]+220.1; tR=0.388 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([NH:27][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(NCc2ccccc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
2,4-Dichloro-6-methyl-3-nitro-pyridine (2 g, 9.7 mmol) and triethylamine (1.35 mL, 9.7 mmol) were dissolved in 40 mL THF and cooled (ice/water) to ˜5° C. A solution of benzylamine (1.04 g, 9.7 mmol) in 10 mL THF was added dropwise and the mixture was then allowed to warm gradually to room temperature overnight. The mixture was evaporated in vacuo, partitioned between EtOAc (50 mL) and water (20 mL). The organic layer was washed with saturated aqueous NaHCO3 (10 mL), dried (MgSO4) and evaporated in vacuo to an orange gum. This gum was preabsorbed onto silica gel and then purified by column chromatography, eluting with DCM:pentane 3:1. Appropriate fractions combined and evaporated in vacuo to yield the title compound as a yellow solid (716 mg).
Reaction SMILES: Cl[C:2]1([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].CCN(C(C)C)C(C)C.[NH2:33][CH2:34][CH2:35][OH:36]>C(Cl)Cl.O>[CH3:17][C:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:18])[C:2]3([NH:33][CH2:34][CH2:35][OH:36])[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: NCCO
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccsc1)C(=O)N2
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(C)c1-c1ccc2c(c1)C(NCCO)(c1ccsc1)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
110 mg (0.33 mmol) Of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-(thiophen-3-yl)indolin-2-one and 220 mg (1.65 mmol) of DIPEA were dissolved in 25 ml of CH2Cl2. After the addition of 55 mg (0.65 mmol) of 2-aminoethanol, the reaction solution was stirred for 16 h at room temperature. Subsequently, the solution was diluted with water. The aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic phases were washed with aqueous NaHCO3 and with water, dried and concentrated in vacuo. The resulting residue was purified by chromatography (eluent: CH2Cl2/MeOH=20/1) to give product (85 mg, 69.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ H 7.48-7.50m, 1H), 7.20-731 (m, 3H), 6.97 (d, J=8.0 Hz, 1H), 4.47 (t, J=5.6 Hz, 1H), 3.20-3.38 (m, 4H), 3.17 (d, J=5.3 Hz, 2H), 2.37 (s, 3H), 2.20 (s, 3H). MS (ESI) m/e [M+1]+ 370.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[N:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH2:35]>>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C@H:11]([CH2:21][C:22]2[C:23]([C:24](=[O:25])[NH:35][CH3:34])=[CH:27][CH:28]=[CH:29][N:30]=2)[O:10][C:9]1([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccccc2F)[C@H](Cc2ncccc2C(=O)O)OC1(C)C
Agent: Cl
Product: CNC(=O)c1cccnc1C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1Cc1ccccc1F

Procedure:
Using general reaction procedure 5 with 2-[(4R,5S)-3-tert-butoxycarbonyl-4-(2-fluoro-benzyl)-2,2-dimethyl-oxazolidin-5-ylmethyl]-nicotinic acid (0.5 g, 1.1 mmol) and methyl amine hydrochloride (0.38 mL, 5.6 mmol) gives the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[C:10](OCC)=[O:11].[H-].C([Al+]CC(C)C)C(C)C>C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][OH:11]
Reactant: CCOC(=O)C(C)(C)CCCCCCCBr
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: CC(C)(CO)CCCCCCCBr
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of ethyl 9-bromo-2,2-dimethylnonanoate (example 103, step a) (1.27 g) in dry diethyl ether (40 mL) at 0° C. under N2 was added diisobutylaluminium hydride (1M in toluene, 9.5 mL) dropwise. The reaction mixture was stirred at 0° C. for 1.25 h then quenched by addition of saturated potassium sodium tartrate solution (150 mL). The mixture was stirred for 15 min then extracted with ethyl acetate (×3) then the combined organics were washed with brine, dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the subtitled compound as a colourless liquid. Yield 0.56 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:44]1([CH:50]2[CH2:54][CH2:53][CH:52]([NH2:55])[CH2:51]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:55][CH:52]4[CH2:53][CH2:54][CH:50]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH2:51]4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: NC1CCC(c2ccccc2)C1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(NC4CCC(c5ccccc5)C4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 27 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with (RS)-3-phenyl-cyclopentylamine (CAS [103858-37-3]; WO2007135026) yielded the title compound (27% yield) as a yellow solid. MS (ISP): m/z=734.5 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C.Cl>O.O1CCCC1.C(O)(C)(C)C>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:15])=[O:11])=[CH:12][CH:13]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(-c2nccs2)cc1
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A mixture of 4-(2-thiazolyl)benzaldehyde (4.6 g, 24 mmol), sodium chlorite (5.5 g, 61 mmols), sodium dihydrogenphosphate (3.2 g, 27 mmols), 2-methyl-2-butene (8.6 g, 120 mmols), tert-butanol (40 ml), tetrahydrofuran (40 ml) and water (20 ml) was stirred at room temperature for 3 hours. The mixture was poured into 1 N hydrochloric acid, and the precipitate formed was taken out through filtration and dried. Thus was obtained a solid of 4-(2-thiazolyl)benzoic acid (4.0 g, 79%).
Reaction SMILES: C1(C[O:8][C:9](=[O:40])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH3:33])[C:24]=3[O:34][CH3:35])=[C:12]([CH2:36][CH2:37][CH3:38])[C:11]=2[OH:39])C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:39][C:11]1[C:12]([CH2:36][CH2:37][CH3:38])=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[C:25]([O:32][CH3:33])[C:24]=2[O:34][CH3:35])[CH:14]=[CH:15][C:10]=1[C:9]([OH:40])=[O:8]
Reactant: CCCc1c(OCCCCCCc2ccc(C(C)C)c(OC)c2OC)ccc(C(=O)OCc2ccccc2)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(C)C)c(OC)c2OC)ccc(C(=O)O)c1O

Procedure:
A solution of 6.96 g of 2-hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylbenzoic acid phenylmethyl ester in 150 mL of ethyl acetate and 1.4 g of 10% palladium on carbon was stirred in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to 5.45 g, mp 106°-108°, of 2-hydroxy-4-[6-[2,3-dimethoxy-4-(1-methylethyl)phenyl]hexyloxy]-3-propylbenzoic acid.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[N:5][C:6]([N:13]2[CH2:16][CH:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]=3)[CH2:14]2)=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].OC1C=CC=C(C(F)(F)F)N=1>>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[N:5][C:6]([N:13]2[CH2:16][CH:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]=3)[CH2:14]2)=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(C(F)(F)F)n2)C1
Agent: Oc1cccc(C(F)(F)F)n1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(C(F)(F)F)n2)C1
Yield: 99.5 %

Procedure:
The title compound (D130) (77 mg) was prepared according to the experimental procedure described in Description 129 starting methyl 5-(trifluoromethyl)-2-(3-((6-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)nicotinate (D89) (80 mg, 0.19 mmol) and 2-Hydroxy-6-(trifluoromethyl)pyridine (55.12 mg, 0.34 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:11]1[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=1.[N+:20]([O-])([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=2)[CH:3]1[C:11]1[C:12]([S:17][CH3:18])=[N:13][CH:14]=[N:15][CH:16]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1ncncc1C1c2ccccc2CC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CSc1ncncc1C1c2cc([N+](=O)[O-])ccc2CC1(C)C

Procedure:
To a solution of 30 g (0.11 mol) of 5-(2,2-dimethylindan-1-yl)-4-methylthiopyrimidine in 500 mL of dichloromethane was added dropwise 100 mL of 90 percent nitric acid. After 1 hr the reaction mixture was poured onto a large volume of ice. The mixture was slowly neutralized with solid potassium carbonate and was then extracted with ether. The organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 36 g of a tan solid. This was recrystallized from 400 mL of ethyl acetate to obtain 12 g of the title compound as a white solid melting at 167°-168° C.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][C:5](OC)=[O:6].[CH3:11][NH2:12]>>[CH3:11][NH:12][C:5](=[O:6])[CH2:4][C:3]([NH2:2])([CH3:10])[CH3:9]
Reactant: COC(=O)CC(C)(C)N
Reactant: CN
Agent: Cl
Product: CNC(=O)CC(C)(C)N

Procedure:
A mixture of methyl 3-amino-3-methyl-butyrate hydrochloride (10.5 g; 62.6 mmoles) and methyl amine (33% solution in ethanol; 55 ml) is refluxed for 18 hours. The solvent is evaporated, the crude is dissolved in methylene chloride (100 ml) and washed with a saturate aqueous solution of sodium chloride (10 ml). After drying over sodium sulphate and evaporation of the solvent to dryness, N-methyl-3-amino-3-methyl-butyramide is obtained; chromatographically pure colorless oil (T.L.C., eluent--methylene chloride:methanol:NH4OH=80:15:1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[CH3:28])=[C:15]([C:29]#[CH:30])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[N:40]([CH3:44])[C:39](=[O:45])[CH:38]=[CH:37]2.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:32])[N:7]([CH3:8])[CH:9]([CH3:31])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[CH3:28])=[C:15]([C:29]#[C:30][C:34]2[CH:35]=[C:36]3[C:41](=[CH:42][CH:43]=2)[N:40]([CH3:44])[C:39](=[O:45])[CH:38]=[CH:37]3)[N:14]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(=O)ccc2cc(Br)ccc21
Reactant: C#Cc1nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)ccc1-c1c(C)nc2ccccn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2c(ccc(=O)n2C)c1

Procedure:
A mixture of tert-butyl-N-[1-[[6-ethynyl-5-(2-methylimidazo[1,2-a]pyridin-3-yl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate F1a (60 mg, 0.14 mmol), 6-bromo-1-methylquinolin-2-one (82 mg, 0.35 mmol), copper(I) iodide (2.6 mg, 0.01 mmol), Dichlorobis(triphenylphosphine)palladium(II) (8.1 mg, 0.01 mmol) and DIPEA (94 μl, 0.55 mmol) is stirred under argon atmosphere in NMP (0.5 ml) for 2 h at 50° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 17 mg (21%). HPLC-MS: M+H=591; tR=1.79 min (*Method—4).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH-].[Na+].[NH2:14][CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1>C1COCC1.O>[CH2:5]([O:4][C:2]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.5 %

Procedure:
Benzyl chloroformate (1.5 mL, 10.5 mmol) and sodium hydroxide (12.5 mL, 1N, 12.5 mmol) were added to a solution of trans-(4-aminomethylcyclohexyl)acetic acid (2.08 g, 10.0 mmol) in THF (32 mL) and H2O (16 mL). The reaction was stirred at RT for 17 hr. The reaction was quenched with 1N HCl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to yield 1.91 g (62%) of product which was carried to the next step without purification. ESI-MS m/z 306 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:30])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:25][CH:26]([CH3:28])[CH3:27])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][C:5]2=[O:29].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([O:1][C:2]1[C:3]([CH3:30])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:25][CH:26]([CH3:28])[CH3:27])([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][C:5]2=[O:29])(=[O:33])[CH3:32]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(COc1ccc([N+](=O)[O-])cc1)(CC(C)C)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(COc1ccc([N+](=O)[O-])cc1)(CC(C)C)O2
Temperature: 25 °C
Reaction time: 35 h

Procedure:
A mixture of 1.5 g of 6-hydroxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 6) and 30 ml of pyridine was mixed with 3 g of acetic anhydride and stirred for 35 hours at room temperature. The reaction mixture was then condensed by evaporation under reduced pressure, mixed with water and extracted with ethyl acetate and benzene. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.I[CH:12]([CH3:14])[CH3:13]>C(O)(C)C.[OH-].[Na+].C(OCC)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH:12]([CH3:14])[CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)I
Reactant: Cc1cc(Br)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cc(Br)cc(C)c1OC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.6 %

Procedure:
A mixture of 4-bromo-2,6-dimethylphenol (4.69 g, 23.3 mmol), 2-iodo-propane (15.81 g, 93.0 mmol) in isopropanol (200 mL) and 1 N aq. NaOH (50 mL) is stirred at rt for 24 h. The mixture is diluted with diethyl ether, washed with 1 N aq. HCl and 1 N aq. NaOH, dried over Na2SO4, filtered and concentrated to give crude 5-bromo-2-isopropoxy-1,3-dimethyl-benzene (4.62 g) as an orange oil; LC-MS: tR=1.07 min. The arylbromide is dissolved in THF (100 mL) and cooled to −78° C. BuLi (15 mL of a 1.6 N solution in hexane) is slowly added (30 min) and the mixture is stirred at −78° C. for 30 min. The mixture is transferred via needle to a cooled (0° C.) solution of dimethylcarbonate (10.7 g, 118.8 mmol) in THF (50 mL). The mixture is stirred for 15 h, quenched with 3 N aq. LiOH (100 mL) and stirred at 60° C. for 24 h. The mixture is diluted with ether (200 mL) and 1M aq. NaOH (100 mL), the phases separated and the org. phase re-extracted with NaOH (50 mL). The aq. phases are washed with diethyl ether (2×50 mL), carefully acidified to pH 3 with 25% HCl. The org. phases are discarded. The aq. phase is extracted with DCM (5×75 mL). The org. extracts are dried over Na2SO4, filtered and evaporated to give 4-isopropoxy-3,5-dimethyl-benzoic acid (2.23 g) as a beige solid; LC-MS: tR=0.91 min, [M+1]+=209.07, 1H NMR (CDCl3): δ 1.34 (d, J=6.3 Hz, 6H), 2.34 (s, 6H), 4.32 (hept, J=6.0 Hz, 1H), 7.81 (s, 2H).
Reaction SMILES: C([O:3]/[CH:4]=[CH:5]/[C:6]1[C:7]([C:38]2[N:39]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:40]3[C:45]([C:46]=2[CH3:47])=[CH:44][CH:43]=[CH:42][CH:41]=3)=[N:8][C:9]([C:12]2[C:13]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[CH:31]=2)=[CH:10][CH:11]=1)C.[BH4-].[Na+].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CCOC(C)=O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[O:19][C:15]3[CH:14]=[C:13]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:34])=[O:35])[C:12]([C:9]4[N:8]=[C:7]([C:38]5[N:39]([C:48]([O:50][C:51]([CH3:54])([CH3:52])[CH3:53])=[O:49])[C:40]6[C:45]([C:46]=5[CH3:47])=[CH:44][CH:43]=[CH:42][CH:41]=6)[C:6]([CH2:5][CH2:4][OH:3])=[CH:11][CH:10]=4)=[CH:31][C:16]=3[C:17]=2[C:27](=[O:30])[NH:28][CH3:29])=[CH:25][CH:24]=1
Reactant: CCO/C=C/c1ccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N(C)S(C)(=O)=O)nc1-c1c(C)c2ccccc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(CCO)c(-c4c(C)c5ccccc5n4C(=O)OC(C)(C)C)n3)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (E)-tert-butyl 2-(3-(2-ethoxyvinyl)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)pyridin-2-yl)-3-methyl-1H-indole-1-carboxylate (72 mg, 0.096 mmol) in THF (0.350 mL) at 0° C. was added Mercuric acetate (36.6 mg, 0.115 mmol) in H2O (0.350 mL). After stirring the resultant mixture at 0° C. for 30 min, NaBH4 (14.47 mg, 0.383 mmol) in 0.580 mL of saturated (aq) K2CO3 solution was added and the reaction mixture was warmed to ambient temperature. After 1.5 h at ambient temperature, the reaction mixture was diluted with EtOAc and washed successively with H2O (2×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-90% EtOAc/CH2Cl2 as eluent. 1H NMR δ (ppm) (CHCl3-d): 8.16 (1H, d, J=8.33 Hz), 8.03˜7.99 (3H, m), 7.87 (1H, d, J=7.99 Hz), 7.69˜7.65 (2H, m), 7.57 (1H, d, J=7.77 Hz), 7.39 (1H, t, J=7.73 Hz), 7.33 (1H, t, J=7.42 Hz), 7.22 (2H, t, J=8.58 Hz), 5.95 (1H, br s), 3.81 (2H, m), 3.19 (3H, s), 3.00 (3H, d, J=4.88 Hz), 2.98˜2.83 (2H, m), 2.78 (3H, s), 2.11 (3H, s), 1.45 (6H, s), 1.27 (3H, s). MS (M+H): 727.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[CH:24]=1.B1(C2C=CC=NC=2)OCCCO1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Reactant: OB(O)c1cccnc1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(C(=O)c2cccc(-c3cccnc3)c2)cnn1-c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (0.9 g, 2.5 mmol) [prepared as described in Example 1 above], pyridine-3-boronic acid, 1,3-propanediol cyclic ester (0.5 g, 3 mmol), potassium phosphate (0.8 g, 3.73 mmol) and tetrakistriphosphine palladium (0.3 g, 0.25 mmol) in dioxane (20 ml) was heated at 85° C. under argon. After 16 h, the reaction mixture was cooled to room temperature and poured into brine. The product was extracted into ethyl acetate, dried over sodium sulfate and filtered. The organic layer was removed in vacuo and the residue was purified by flash chromatography (elution gradient: 40-80% ethyl acetate/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-3-yl)benzoyl]-pyrazole (0.50 g) which was recrystallized from ethyl acetate (mpt. 222.2-223.0).