Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH2:24][S:25][CH:26]([CH3:28])[CH3:27])[CH:7]=1)[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([Cl:30])=[CH:32][CH:33]=3)=[CH:17][C:16]=2[CH2:24][S:25][CH:26]([CH3:28])[CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CSC(C)C)c1

Procedure:
[3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester was reduced to the amine according to the procedure described in Example 11, Step 2. The amine was treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-Chloro-benzoylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester as outlined in Example 11, Step 4 provided the acid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:8][CH2:7][C:6]([CH2:10][CH2:11][CH2:12][C:13]#[C:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])([OH:9])[CH2:5][CH2:4]1.I[C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33].C(=O)([O-])[O-].[Na+].[Na+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-2](Cl)C1C(Cl)=CC=CN=1)(C)C.O=O>[CH3:29][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:4][CH2:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]2[C:34]3[C:32](=[CH:31][CH:37]=[CH:36][CH:35]=3)[NH:33][C:14]=2[Si:15]([CH2:20][CH3:21])([CH2:16][CH3:17])[CH2:18][CH3:19])([OH:9])[CH2:7][CH2:8]1
Reactant: Nc1ccccc1I
Reactant: CC[Si](C#CCCCC1(O)CCC(c2cccc(F)c2)(N(C)C)CC1)(CC)CC
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-2](Cl)c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: O=O
Product: CC[Si](CC)(CC)c1[nH]c2ccccc2c1CCCC1(O)CCC(c2cccc(F)c2)(N(C)C)CC1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
A mixture of 4-dimethylamino-4-(3-fluorophenyl)-1-(5-(triethylsilyl)pent-4-inyl)cyclohexanol (970 mg, 2.32 mmol), 2-iodoaniline (609 mg, 2.78 mmol), [1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)palladium(II)-chloride (PEPPSI, 156 mg, 0.23 mmol) and sodium carbonate (1.23 g, 11.6 mmol) was degasified, mixed with oxygen-free N,N-dimethylformamide (10 mL) in argon and stirred for 7 h at 100° C. The reaction mixture was then concentrated to low volume in a vacuum, the residue repeatedly taken up in toluol (10 mL) and concentrated to low volume in a vacuum again each time. This residue was distributed between ethyl acetate (30 mL) and water (30 mL), the organic phase was washed with water (2×15 mL) and sodium thiosulphate solution (2×15 mL), dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product was purified by means of flash chromatography (100 g, 20×4.0 cm) with cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:15][C:16](=[CH2:20])[C:17](Cl)=[O:18]>ClCCl>[CH3:15][CH:16]1[C:17](=[O:18])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH:8]=[CH:7][C:6]=2[CH2:20]1
Reactant: C=C(C)C(=O)Cl
Reactant: c1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2ccc3ccccc3c2C1=O
Temperature: -30 °C
Yield: 84 %

Procedure:
Aluminum chloride powder (240 g) was added to a dry round-bottomed flask under nitrogen, after which 1 l of dichloromethane was added. The suspension was cooled to -30° C., and 100 g of naphthalene and 90.5 g of freshly distilled 2-methyl-2-propenoyl chloride in 950 ml of dichloromethane were added dropwise under nitrogen in 1.5 h. The reaction mixture was stirred for another hour at -30° C., after which the cold reaction mixture was poured into 10 l of ice water. The organic layer was separated, the water layer was extracted with dichloromethane, and the combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to dryness. The crude product was distilled at 200° C./33 Pa, after which 127 g (84%) of 2,3-dihydro-2-methyl-1H-benz[e]indene-1-one were obtained with a purity >95% (GLC).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Product: Cc1cn(C)c2c(Nc3cccc(F)c3)ncc(C(=O)N3CCOCC3)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and using 3-fluoroaniline (130 ul) instead of 3-bromoaniline and heating for 15 rather than 30 minutes to give 1-[7-(3-fluoro-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (89 mg).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1cccnc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccnc3)cc2F)cn1
Yield: 82.1 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 2-(pyridin-3-yl)ethylamine (0.019 g, 0.154 mmol) gives the title compound (0.0463 g, 82.2%): TOF MS ES+ 367.2 (M+H)+, HRMS calcd for C20H20N4O2F 367.1570 (M+H)*, found 367.1553, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.9 min. 100% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[C:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[O:14]=[C:13]1[NH:15][C:26]2([CH2:27][CH2:28][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24][CH2:25]2)[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 70 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), N-Boc-piperidin-4-one (0.600 mg, 3.00 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 1 h at 70° C. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (3:1, 100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave a solid. The solid was triturated with ethyl acetate-dichloromethane, and the precipitate was collected by filtration to afford the title compound (0.184 g, 92%) as a yellow solid:
Reaction SMILES: N1CCOCC1.C([O:10][C:11]([C@H:13]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:14]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:12])C=C>O1CCCC1.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>[C:11]([C@H:13]([CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:14]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]([O:17][CH3:18])=[O:16])([OH:12])=[O:10]
Reactant: C=CCOC(=O)[C@H](CC(C)C)[C@H](OCc1ccccc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](OCc1ccccc1)[C@@H](CC(C)C)C(=O)O
Reaction time: 0.5 h
Yield: 121.2 %

Procedure:
0.39 ml of morpholine and 0.05 g of tetrakis(triphenylphosphine)palladium(0) were added to a stirred solution of 0.15 g of methyl 3(R)-(allyloxycarbonyl)-2(S)-benzyloxy-5-methylhexanoate in 5 ml of tetrahydrofuran under a nitrogen atmosphere. After stirring the mixture for 0.5 hour the solvent was evaporated. The residue was dissolved in dichloromethane and washed in succession with 2M aqueous hydrochloric acid and water. The organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was dissolved in diethyl ether and filtered. The diethyl ether solution was evaporated to give 0.16 g of methyl 3(R)-carboxy-2(S)-benzyloxy-5-methylhexanoate in the form of a yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[CH:11][C:10]=2[CH3:22])O1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([C:35]3[CH:36]=[C:37]([CH:42]=[CH:43][C:44]=3[CH3:45])[C:38]([O:40][CH3:41])=[O:39])=[CH:32][CH:33]=2)[CH:28]=[N:27][N:26]=1>>[CH3:45][C:44]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][C:35]=1[C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][CH:32]=1)[C:25]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]([F:19])([F:20])[F:21])(=[O:16])=[O:17])=[CH:11][C:10]=1[CH3:22])=[N:26][N:27]=[CH:28]2
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Reactant: Cc1cc(S(=O)(=O)C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1ccc(C)c(-c2ccc3c(-c4ccc(S(=O)(=O)C(F)(F)F)cc4C)nncc3c2)c1

Procedure:
Methyl 4-methyl-3-(1-(2-methyl-4-(trifluoromethylsulfonyl)phenyl)phthalazin-6-yl)benzoate was prepared according to the procedure described in Example 223, using 4,4,5,5-tetramethyl-2-(2-methyl-4-(trifluoromethylsulfonyl)phenyl)-1,3,2-dioxaborolane and methyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate as starting materials. MS (ESI, pos. ion) m/z: 500.9 (M+1).
Reaction SMILES: [C:1]([C:9]1[C:10]([OH:22])=[C:11]([C:16]([CH3:21])=[CH:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24](=[CH:26][CH2:27][CH2:28][CH:29]([CH2:31][CH2:32]O)[CH3:30])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1>[CH3:30][CH:29]([CH2:28][CH2:27][CH2:26][C:24]([CH3:25])=[CH2:23])[CH2:31][CH2:32][O:19][C:18](=[O:20])/[CH:17]=[C:16](/[C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[OH:22])\[CH3:21]
Reactant: CC(=CC(=O)O)c1ccc(O)c(C(=O)c2ccccc2)c1O
Reactant: CC(C)=CCCC(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: C=C(C)CCCC(C)CCOC(=O)/C=C(\C)c1ccc(O)c(C(=O)c2ccccc2)c1O

Procedure:
A solution of 3-(3-benzoyl-2,4-dihydroxyphenyl)-but-2-enoic acid (5.97 g, 20.0 mmol), citronellol (3.13 g, 20.0 mmol) and p-toluenesulfonic acid (1 g) in cyclohexane (150 mL) is refluxed for 6 h under vacuum using a Dean Stark separator. The reaction mixture is partitioned between methylene chloride (150 mL) and water (150 mL); the organic layer is removed and washed with methylene chloride (100 mL). The combined organic layers are washed sequentially with saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to give (E)-3-(3-benzoyl-2,4-dihydroxyphenyl)-but-2-enoic acid 3,7-dimethyl-oct-7-enyl ester as an oil which can be purified by flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)=[C:4]([F:13])[CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CC(C)=O>[F:13][C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH:10]([OH:12])[CH2:11]1
Reactant: Nc1ccc(N2CC(O)C2)c(F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-(4-amino-2-fluorophenyl)azetidin-3-ol (1.8 g, 9.94 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.57 g, 19.87 mmol, 2.0 eq) and phenyl chloroformate (1.71 g, 10.89 mmol, 1.1 eq) and stirred at RT for 2 h. The reaction mixture was evaporated, diluted with EtOAc (100 mL), washed with water (100 mL) followed by brine and evaporated. The residue obtained was purified by CC (eluent: EtOAc/PE (1:4)) to obtain phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (2.3 g, 76%, brown solid) (TLC: EtOAc/PE (1:1), Rf: 0.45).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1ccn2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of methyl indole-4-carboxylate (10.0 g, 57.14 mmol) was added sodium hydride (60% dispersion in mineral oil (5.71 g, 142.8 mmol) in DMF (200 mL) in portions. The mixture was stirred under an atmosphere of nitrogen for 20 minutes. To this was added benzyl bromide (8.48 mL, 74.4 mmol) and the mixture continued to stir for 16 hours. The mixture was poured into an ice/water mixture and extracted with diethyl ether (3×500 mL). The combined organic layers were washed with brine (3×200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (silica gel, 5 to 15% ethyl acetate in hexanes) afforded methyl 1-benzyl-1H-indole-4-carboxylate (A1b, 13.89 g, 92%) as a pale yellow oil, which crystallized upon standing: 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.30-7.25 (m, 4H), 7.20-7.16 (m, 2H), 7.10-7.05 (m, 2H), 5.36 (s, 2H), 3.98 (s, 3H); MS (ESI+) m/z 266 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]([F:30])[F:29])=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH:11]=[CH:10][C:9]=1[CH3:31])(=O)=O.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]1>CN(C=O)C>[F:30][CH:28]([F:29])[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[N:20][C:15]([NH:14][C:12]3[CH:11]=[CH:10][C:9]([CH3:31])=[C:8]([CH:13]=3)[CH2:7][CH2:6][N:32]3[CH2:37][CH2:36][CH:35]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:34][CH2:33]3)=[N:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1CCOS(C)(=O)=O
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCc2cc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)ccc2C)CC1
Temperature: 90 °C

Procedure:
5-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl methanesulfonate 51b (0.9 mmol), ethyl piperidine-4-carboxylate (2.2 mmol) are dissolved in DMF (10 mL) and heated to 90° C. for 4 h then cooled to rt. The reaction mixture is partitioned with EtOAc and water. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. The crude material is purified by column chromatography on silica with hexane:EtOAc=1:1 to 100% EtOAc as eluant to yield ethyl 1-(5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)-2-methylphenethyl)piperidine-4-carboxylate 52 as clear viscous oil. MS (m/z) (M+1)+: 511.2.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[N:8]1.[OH:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])[CH2:26][O:27][C:23]=2[C:22]=1[CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.N1CCCCC1>CO>[OH:20][C:21]1[CH:30]=[CH:29][C:24]2[C:25](=[O:28])/[C:26](=[CH:16]/[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:19])([CH3:18])[CH3:1])[N:8]=3)/[O:27][C:23]=2[C:22]=1[CH2:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1nc(C=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 53.9 %

Procedure:
A solution of the positional isomer (2) of N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-3-carboxaldehyde (0.354 g, 1.28 mmol) obtained in Step 1 in methanol (5 mL) was added with tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.446 g, 1.28 mmol) and piperidine (0.0109 g, 0.128 mmol), and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.419 g, 53%).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[S:12][CH:11]=[N:10][CH:9]=1.[OH:13][C:14]([CH3:47])([CH3:46])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>CN(C)C=O>[OH:13][C:14]([CH3:46])([CH3:47])[CH2:15][C@@:16]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:8]3[S:12][CH:11]=[N:10][CH:9]=3)=[CH:29][CH:30]=2)[CH3:24])[CH2:18][CH2:17]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cncs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](c1ccc(-c2cncs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 M aqueous Na2CO3 solution (0.63 mL) was added to a solution of 5-bromo-thiazole (70 μL) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.30 g) in dimethylformamide (3 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (15 mg) was added. The mixture was heated to 90° C. and stirred at this temperature for 2 h. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 50:50->0:100) to afford the title compound as a solid. Yield: 0.19 g (70% of theory); Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([O:35][C:36]([O:38][CH2:39][CH:40]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]3[C:41]2=[CH:42][CH:43]=[CH:44][CH:45]=3)=O)C(=O)C1>>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][N:10]([C:36]([O:38][CH2:39][CH:40]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:46]=2[C:47]2[C:52]1=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:35])[CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:16][CH2:17]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)N1CCC(CNC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Product: CC(C)N1CCC(CN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Yield: 113.5 %

Procedure:
Using coupling method B, N-[(R)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-1-phenylethyl]carbamic acid tert-butyl ester (1.1 g, 2.8 mmol) and 9-fluorenylmethyl N-succinimidyl carbonate (Fmoc-OSu, 962 mg, 2.9 mmol) afforded 1.9 g of the title compound as a crude residue, that was used without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1[N:20]=[C:21]([CH2:24]Cl)[S:22][CH:23]=1)=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([CH2:24][C:21]2[S:22][CH:23]=[C:19]([C:17]([O:16][CH2:14][CH3:15])=[O:18])[N:20]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1csc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1csc(CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Yield: 126.8 %

Procedure:
tert-Butyl 1-piperazinecarboxylate (1.811 g, 9.72 mmol), 2-chloromethyl-thiazole-4-carboxylic acid ethyl ester (2 g, 9.72 mmol), potassium carbonate (2.69 g, 19.45 mmol) and sodium iodide (0.292 g, 1.945 mmol) were combined and stirred in acetonitrile at reflux for 2 hours. The reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane and filtered. The filtrate was concentrated under reduced pressure to give the title compound (4.38 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCCCCC>[Cl:23][CH2:24][C:25]([O:22][C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]1[C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:26]
Reactant: O[C@@H]1CCCC[C@H]1c1cc(Cl)ccc1OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CCl)O[C@@H]1CCCC[C@H]1c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 118.7 %

Procedure:
In a 1 L round bottom flask equipped with a magnetic stirrer, thermometer and condenser is placed 50 g (0.15 mol) of trans-2-(2'-benzyloxy-5'-chlorophenyl)cyclohexanol. This is dissolved in 200 ml of methylenechloride, and then 18 g (0.16 mol) of chloracetyl chloride is added followed by 0.14 g (0.001 mol) of 4-dimethylaminopyridine. The mixture is heated to reflux and monitored by TLC (20% ethyl acetate, hexane). After 4 hours TLC shows the reaction to be complete, it is cooled to room temperature and 200 ml of saturated sodium bicarbonate is added. The reaction mixture is stirred rapidly for another 3 hours. The organic phase is then separated, dried with anhydrous potassium carbonate, filtered and evaporated under reduced pressure to yield 70 g of an amber oil. This oil is dissolved in 100 ml of hexane from which it crystallizes to afford 47 g of an off-white solid trans-2-(2'-benzyloxy-5'-chloro-phenyl)cyclohexyl chloroacetate, which is used directly in the next step.