Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][N:26]([CH3:52])[CH2:27][CH2:28][CH:29]([NH:39][C:40]([NH:42][C:43]1[CH:44]=[C:45]2[C:49](=[CH:50][CH:51]=1)[CH2:48][CH2:47][CH2:46]2)=[O:41])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.[C:53]1([NH2:60])[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH2:59].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[NH:60][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([CH:29]([NH:39][C:40]([NH:42][C:43]2[CH:44]=[C:45]3[C:49](=[CH:50][CH:51]=2)[CH2:48][CH2:47][CH2:46]3)=[O:41])[CH2:28][CH2:27][N:26]([CH3:52])[CH3:25])=[CH:38][CH:37]=1
Reactant: Nc1ccccc1N
Reactant: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCC(NC(=O)Nc1ccc2c(c1)CCC2)c1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
HATU (250 mg, 0.66 mmol) was added to a solution of 4-[1-(2-dimethylaminoethyl)-3-(indan-5yl)ureidomethyl] benzoic acid (Reference Compound No. 10-1, 250 mg, 0.66 mmol), o-phenylenediamine (140 mg, 1.3 mmol), and N,N-diisopropylethylamine (0.33 mL, 2.0 mmol) in DMF (5.0 mL), and then the mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added thereto, and then the whole was washed with brine (50 mL) three times. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. After the residue was purified by silica gel column chromatography (chloroform-methanol), the resulting solid was collected by filtration with ethyl acetate, and then it was dried under reduced pressure to give 230 mg of the title compound as a pale yellow-white solid. (Yield 74%)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=O)=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22](=[O:24])[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Yield: 99.1 %

Procedure:
A mixture of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid (300 mg, 0.84 mmol), aniline (0.15 mL, 1.70 mmol), DMAP (60 mg, 0.50 mmol) and EDC.HCI (320 mg, 1.70 mmol) in CH2Cl2 (30 mL) was stirred at room temperature for 66 h. The reaction mixture was concentrated under vacuum and the residue was subjected to flash silica gel column chromatography eluting with methanol/CH2Cl2 (1:99, v/v) to give the desired amide 18 as a white solid (360 mg, 99% yield). 1H NMR (300 MHz, CDCl3) δ 8 1.55 (m, 4H), 2.60 (m, 2H), 3.20 (m, 2H), 4.58 (s, 2H), 4.70 (br s, 1H), 5.10 (s, 2H), 6.88 (d, 2H), 7.15. (m, 3H), 7.35 (m, 7H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 433 [C26H28N2O4 +H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([C:12]([F:15])([F:14])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[CH2:1]([O:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]([F:14])([F:15])[F:13])[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncnc(C(F)(F)F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ncnc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of 3.82 g (17.2 mmoles) of 4-ethoxy-6-trifluoromethylpyrimidine-5-carboaldehyde dissolved in 50 ml of methanol was added, with ice-cooling, into a solution of 1.7 g (45.7 mmoles) of sodium borohydride dissolved in 50 ml of methanol. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 3.77 g (yield: 97.8%) of (4-ethoxy-6-trifluoromethylpyrimidin-5-yl)-methanol.
Reaction SMILES: I[C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC.C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OC(C)C)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH:20]([C:2]1[N:6]([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9][C:8]2([CH3:19])[CH3:18])[CH:5]=[N:4][CH:3]=1)=[CH2:21]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: C=Cc1cncn1C1c2ccccc2C(=O)OC1(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
DMF (30 mL) is added to 4-(5-iodo-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (1.62 g, 4.18 mmol) (Example 2b), tributylvinyltin (2.40 g, 8.36 mmol), Pd2 dba3.CHCl3 (0.087 g, 0.084 mmol) and triphenylphosphine (0.089 g, 0.334 mmol) under nitrogen. The mixture is heated to 90° C., to give a clear tan solution. After 3 h, the mixture is cooled down, diluted with isopropyl acetate and washed twice with water and brine. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. The residue is purified by silica gel flash chromatography (10% wt silica gel/KF, elution with dichloromethane-methanol, 49:1 to 24:1) to give 4-(5-vinyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a yellow solid; MS (ESI) m/z 269.2 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.20 (s, 3 H), 1.51 (s, 3 H), 5.42 (br. s, 1 H), 5.69 (s, 1 H), 5.81 (br. s, 1 H), 6.95 (br. s, 1 H), 7.14 (br. s, 1H), 7.21 (s, 1 H), 7.42 (d, J=7.6 Hz, 1 H), 7.58-7.69 (m, 1 H), 7.70-7.80 (m, 1 H), 8.21 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:3]=[N:2]1.Cl.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=2)=[O:22])[CH2:17][CH2:16]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[O:22])[CH2:19][CH2:20]2)=[O:12])[N:3]=[N:2]1
Reactant: O=C(O)CCCCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5-(1H-1,2,3-Triazol-4-yl)entanoic acid (step 3) (50 mg, 0.294 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (Example 17, step 2) (100 mg, 0.294 mmol) were dissolved in DMF (1 ml). DIPEA (257 μl, 1.472 mmol) was added followed by 50% T3P® solution in DMF (344 μl, 0.589 mmol). The reaction mixture was stirred at RT for 96 hrs and concentrated under reduced pressure. The crude product was dissolved in DCM and washed with 10% citric acid. The organic portion was separated, dried over MgSO4 (anh), filtered and evaporated under reduced pressure. Purification by preparative HPLC afforded product fractions that were concentrated to afford a residue. The residue was dissolved in DCM and washed with a minimal volume of water, dried over MgSO4 (anh) filtered and evaporated under reduced pressure to afford the title compound;
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH2:9]([O:11][C:12](=[O:27])[CH2:13][N:14]([CH2:23][CH2:24][CH:25]=[CH2:26])[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH3:10].C([Cu])#N.[Li+].[Cl-].C(Br)C=C>C1COCC1.CCOCC.[Zn+2].[Br-].[Br-]>[CH2:9]([O:11][C:12]([C@@H:13]1[C@H:25]([CH2:26][CH2:4][CH:3]=[CH2:2])[CH2:24][CH2:23][N:14]1[C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])=[O:27])[CH3:10]
Reactant: C=CCCN(CC(=O)OCC)[C@@H](C)c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: N#C[Cu]
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC[C@@H]1CCN([C@@H](C)c2ccccc2)[C@@H]1C(=O)OCC
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of diisopropylamine(3.6 g, 35.7 mmol) in THF(80 mL) at −40° C. is added BuLi(14.28 mL, 35.7 mmol, 2.5 M in hexane) slowly. The solution is warmed to 0° C. and stirred for 30 min to form an LDA solution. The LDA solution is cooled to −70° C. and added to a solution of [But-3-enyl-((S)-1-phenyl-ethyl)-amino]-acetic acid ethyl ester(7.8 g, 29.8 mmol) in THF (80 mL) slowly at −70° C. The light yellowish reaction solution is stirred at −20° C. for 30 min to become a deep yellow solution, and then cooled to −70° C. To the solution is added **ZnBr2**(16.76 g, 74.5 mmol) in ether (50 mL) dropwise at −70° C. After stirring at RT for 1.5 hrs, the reaction solution is cooled to 0° C. and added a solution of CuCN(3.47 g, 38.74 mmol) and LiCl(3.29 g, 77.48 mmol) in THF(80 mL) slowly. After stirring at 0° C. for 10 min, allyl bromide(7.26 g, 60 mmol) is added dropwise to the reaction solution, and warmed very slowly to r.t. After stirring overnight at r.t., the reaction is quenched by addition of 60 mL of saturated NH4Cl and extracted with 3×150 mL of ether. The combined organic layers is concentrated. The crude product is purified by chromatography (hexane/EtOAc: 85/15) to give a colorless liquid(7.4 g, 82.6%). (NMR and MS data confirmed, U-4117-40-19, U-4117-34-35). ** ZnBr2** is dried at 150° C. under high vacuum for 1 hour before used**
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.CC1(C)C(C)(C)OB([C:47]2[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:59])=[O:58])[CH:53]=[C:52]3[C:48]=2[CH:49]=[N:50][NH:51]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:47]4[CH:55]=[C:54]([NH:56][S:57]([CH3:60])(=[O:58])=[O:59])[CH:53]=[C:52]5[C:48]=4[CH:49]=[N:50][NH:51]5)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ncc23)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc5[nH]ncc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 44.8 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (25 mg, 0.04 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methanesulfonamide (35 mg, 0.10 mmol), sodium carbonate (11 mg, 0.10 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) and 2 ml 1,2-dimethoxyethane and 1 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 13 mg (42% yield) of the title compound. Purity 98%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH:11]=[O:12].CI.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O>[CH3:15][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:11]=[O:12])[CH:4]=1
Reactant: O=Cc1cc(C(=O)O)ccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of 4-fluoro-3-formyl-benzoic acid (800 mg, 4.8 mmol) in DMF (10 mL), are added MeI (0.35 mL, 5.7 mmol) and K2CO3 (790 mg, 5.7 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is diluted with EtOAc (20 mL) and water (10 mL). The organic layer is separated, washed with brine, dried under anhy. Na2SO4 (500 mg), filtered and is concentrated. The residue is purified by silica gel flash chromatography with 0-20% EtOAc/heptane as the eluent. The product fractions are collected and concentrated to afford 4-fluoro-3-formyl-benzoic acid methyl ester (710 mg, 82%).
Reaction SMILES: O[C:2]1[C:3]2[CH:11]=[CH:10][N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][CH2:31][NH:32]2)=[CH:28][CH:27]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C=O)C>[Cl:25][C:26]1[CH:34]=[C:33]2[C:29]([CH2:30][CH2:31][N:32]2[C:2]2[C:3]3[CH:11]=[CH:10][N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:28][CH:27]=1
Reactant: Oc1ncnc2cnccc12
Reactant: Clc1ccc2c(c1)NCC2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Clc1ccc2c(c1)N(c1ncnc3cnccc13)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
To a suspension of 4-hydroxy-pyrido[3,4-d]pyrimidine (0.103 g, 0.70 mmol) in dry pyridine (2 ml) cooled in an ice-water bath was added dropwise trifluoroacetic anhydride (0.20 ml, 1.4 mmol). After stirring for 0.5 hour, 6-chloroindoline (0.10 g, 0.66 mmol) and pyridine (0.14 g, 1.81 mmol) in dry DMF (1.5 ml) was added dropwise. The cold bath was allowed to warm to ambient temperature and then heated at 70° C. for 3 hours. The reaction was cooled to ambient temperature and then added to methylene chloride (150 mL). The organic layer was washed with saturated sodium carbonate and water, and then dried over sodium sulfate. The solvent was removed by rotary evaporation and the residue purified by column chromatography (silica gel, 9/2/1-CH2Cl2/hexanes/methanol) to give a pale yellow residue (0.048 g, 28%): MP: 194-6° C.; LC/MS: 283 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:5](S(N(C)C)(=O)=O)[CH:6]=[CH:7][N:8]=2)[CH2:3][CH2:2]1.C([Li])CCC.CN([CH:23]=[O:24])C.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([C:4]2[NH:5][CH:6]=[C:7]([CH:23]=[O:24])[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)n1ccnc1C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c[nH]c(C2CC2)n1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Into a 500-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-cyclopropyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (compound 238.2, 5 g, 23.23 mmol) in tetrahydrofuran (100 mL). This was followed by the addition of n-butyllithium (11.2 mL, 2.5M in THF) dropwise at −78° C. over a period of 30 min. To this was added DMF (11.8 mL, 152.55 mmol). The resulting solution was stirred for 30 min at −50° C., then hydrogen chloride (50 mL, 1M) was added. The reaction mixture was stirred for 2 h at room temperature. The pH of the solution was adjusted to 7-8 with sodium bicarbonate (sat). The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 3 g (97%) of the title compound as a white solid.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CC)C(C)C)(C)C.[CH2:14]([O:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([Br:32])=[C:27]([CH3:33])[CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C1(C)C=CC=CC=1>[CH2:14]([O:21][CH2:22][CH2:23][N:24]([C:25]1[CH:26]=[C:27]([CH3:33])[C:28]([Br:32])=[C:29]([CH3:31])[CH:30]=1)[C:1]([Cl:4])=[O:2])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(NCCOCc2ccccc2)cc(C)c1Br
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N(CCOCc2ccccc2)C(=O)Cl)cc(C)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Phosgene (3.5 ml, 6.64 mmol, 20% solution in toluene) and N,N-diisopropylethylamine (1.2 ml, 6.64 mmol) were added to a solution of N-(2-(benzyloxy)ethyl)-4-bromo-3,5-dimethylaniline (740 mg, 2.21 mmol) in anhydrous toluene (11 ml) at 0° C. The reaction solution was gradually warmed to room temperature and stirred at the same temperature for three hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane) to give N-(2-(benzyloxy)ethyl)-N-(4-bromo-3,5-dimethylphenyl)carbamic acid chloride (860 mg, 98%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].N[C@H](C(O)=O)CCSC.[OH-].[Na+].C(=O)(O)[O-].[Na+]>CS(O)(=O)=O.O>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Oc2ccc3c(cnn3C(C)C)c2)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Solvent: O
Product: CC(C)n1ncc2cc(Oc3ccc(O)cc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.2 %

Procedure:
A solution of 1-Isopropyl-5-(4-methoxy-phenoxy)-1H-indazole (0.090 grams, mmol) in 2 mL of methanesulfonic acid was treated with 0.15 grams of methionine. After stirring for 24 hours at room temperature, the mixture was treated with 1.2 grams of sodium hydroxide in 25 mL of water with cooling in an ice bath, neutralized with aqueous sodium bicarbonate, extracted 3 times with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo, affording 0.090 grams of 4-(1-isopropyl-1H-indazol-5-yloxy)-phenol as a colorless syrup. MS: 269.7 [M+H]+
Reaction SMILES: [Si]([O:8][C@H:9]1[C@@H:16]2[N:12](/[C:13](=[N:21]/[C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[C:23]=3[CH3:31])/[O:14][C@@H:15]2[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[OH:8][C@H:9]1[C@@H:16]2[N:12](/[C:13](=[N:21]/[C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([Cl:30])[C:23]=3[CH3:31])/[O:14][C@@H:15]2[C:17]([F:18])([F:20])[F:19])[CH2:11][CH2:10]1
Reactant: Cc1c(/N=C2\O[C@H](C(F)(F)F)[C@@H]3[C@H](O[Si](C)(C)C(C)(C)C)CCN23)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(/N=C2\O[C@H](C(F)(F)F)[C@@H]3[C@H](O)CCN23)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To 7G (140 mg, 0.296 mmol) in THF (2 mL) was added a 1 M THF solution of TBAF (0.400 1 nL, 0.400 mmol). After stirring at rt for 2 h, saturated aqueous ammonium chloride and EtOAc were added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified twice via preparative HPLC (YMC ODS C-1 8, 30×100 mm, eluting with 50-80% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min; Flow rate at 40 mL/min; UV detection at 220 nm) to provide the title compound (50.0 mg) as a white foam. MS: m/z 358 [M−H]−.
Reaction SMILES: [N:1]1([CH2:5][C@@H:6]([NH2:10])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1.[CH:11](=O)[CH3:12].[Na].O>C(Cl)Cl>[N:1]1([CH2:5][C@@H:6]([NH:10][CH2:11][CH3:12])[CH:7]([CH3:9])[CH3:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC=O
Reactant: CC(C)[C@H](N)CN1CCC1
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: CCN[C@H](CN1CCC1)C(C)C
Yield: 19.9 %

Procedure:
(S)-1-(Azetidin-1-yl)-3-methylbutan-2-amine (Compound U) (0.420 g, 2.95 mmol) and acetaldehyde (0.166 mL, 2.95 mmol) was mixed in DCM (10 mL). Sodium triacetoxyhydroborate (0.813 g, 3.84 mmol) was added in small portions and the resultant mixture was stirred at rt for 5 h. Water was added and the pH was adjusted to pH9. The water phase was extracted with DCM (4×50 mL). The combined organic layers were combined and washed with brine, passed through phase separator and evaporated under reduced pressure to give the title compound (0.1 g, 20%). The obtained crude product was used without further purification. LCMS (M+H)+: 171.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][OH:16])[CH2:12][CH2:11]2)[CH2:4][O:3]1.Cl[CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21].[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1([CH3:17])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH:10]2[O:14][CH:13]([CH2:15][O:16][CH2:19][C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[O:21])[CH2:12][CH2:11]2)[CH2:4][O:3]1
Reactant: CC1(C)OCC(COCC2CCC(CO)O2)O1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCN(CCC)C(=O)COCC1CCC(COCC2COC(C)(C)O2)O1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of 4.93 g of 5-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]methyl]tetrahydro-2-furan-methanol (0.02 mole) and 3.55 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) are dissolved in 125 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4× 300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is then removed in vacuo yielding a pale yellow oil which is vacuum distilled through a 10 cm vigreux column and the fraction distilling at 91°-94° @ 0.4 mm is collected, yielding 4.86 g (63%) of the above compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH:8]([NH:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[CH:9]=[O:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCOC(=O)NC(CC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC(=O)NC(C=O)CC(=O)OC(C)(C)C
Yield: 91 %

Procedure:
A solution of 3-allyloxycarbonylamino-N-methoxy-N-methyl-succinamic acid tert-butyl ester, 101, (24.3 g, 76.8 mmol) in THF (60 mL) is treated at −78° C. with lithium aluminum hydride (1 M in THF, 39 mL, 39 mmol) dissolved in ether (200 mL) over 5 minutes. After the consumption of starting material, the solution is cautiously quenched with 1.0 N HCl, washed with 1.0 N HCl (2×100 mL) and brine (1×150 mL). The organic layer is concentrated in vacuo to afford 18.2 g (91% yield) of the desired product as a clear oil.