Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:52])[C:3]1[C:7]([CH:8]=O)=[C:6]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:28]4[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:48])=[N:31][N:32]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][C@@H:21]([O:24][CH3:25])[C:20]([CH3:27])([CH3:26])[CH2:19]4)[C:12]=3[CH2:11]2)[N:5]([CH3:51])[N:4]=1.Cl.[NH2:54]O.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:52][CH:2]([F:1])[C:3]1[C:7]([C:8]#[N:54])=[C:6]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:28]4[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:48])=[N:31][NH:32]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][C@@H:21]([O:24][CH3:25])[C:20]([CH3:26])([CH3:27])[CH2:19]4)[C:12]=3[CH2:11]2)[N:5]([CH3:51])[N:4]=1
Reactant: NO
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(C=O)c(C(F)F)nn2C)CC3)CC1(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2c(C#N)c(C(F)F)nn2C)CC3)CC1(C)C
Temperature: 25 °C

Procedure:
A vessel was charged with (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde (54 mg, 0.074 mmol), hydroxylamine hydrochloride (77 mg, 1.105 mmol), and DMSO (491 μL). The vessel was capped and placed in a sand bath preheated to 100° C. and the reaction mixture was stirred at that temperature. After 2 h the mixture was diluted with methanol and transferred to a round-bottomed flask. Potassium carbonate was added, and the mixture stirred for 2 h at 60° C., then allowed to cool to room temperature. The mixture was then filtered through Celite and concentrated, redissolved in methanol, filtered through a syringe filter, and purified by HPLC (15-100% CH3CN in water with 0.1% NH4OH) to provide (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbonitrile. 1H NMR (400 MHz, CD3OD) δ ppm 7.44 (d, J=8.6 Hz, 1 H), 7.31 (d, J=8.6 Hz, 1 H), 6.54-6.92 (m, 1 H), 4.64 (d, J=14.8 Hz, 1 H), 4.53 (d, J=14.8 Hz, 1 H), 3.85-3.95 (m, 1 H), 3.80 (s, 3 H), 3.67-3.75 (m, 2 H), 3.52 (dd, J=13.4, 1.3 Hz, 1 H), 3.37 (s, 3 H), 3.01-3.10 (m, 4 H), 2.26 (s, 3 H), 2.01 (s, 3 H), 1.97-2.06 (m, 1 H), 1.67-1.79 (m, 1 H), 1.01 (s, 3 H), 0.93 (s, 3 H); MS (ESI+) m/z 576.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2B1OC(C)(C)C(C)(C)O1.Cl[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C@@H:47]2[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]2)[N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C@@H:47]2[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]2)[N:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Reactant: COc1cc(Cl)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (600 mg, 1.17 mmol), and (R)-tert-butyl 3-((4-chloro-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (483 mg, 1.41 mmol) in DME (12 mL) and water (3 mL) was added Pd(PPh3)4 (270 mg, 0.234 mmol) and Na2CO3 (372 mg, 3.51 mmol) and argon gas was bubbled for 15 min. The above mixture was heated at 90° C. for 8 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 30% EtOAc in petroleum ether) to give (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (500 mg, 62.5%). MS (ESI, pos. ion) m/z: 690.2 (M+1); 1H-NMR (400 MHz CDCl3): δ ppm 8.16 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.84-7.90 (m, 3H), 7.26-7.46 (m, 6H), 7.02 (m, 2H), 6.41 (s, 1H), 5.07 (brs, 1H), 4.10-4.14 (m, 1H), 3.93 (s, 3H), 2.37 (s, 3H), 1.25-1.60 (m, 15H).
Reaction SMILES: [CH2:1]([N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[C:6](=[O:9])[CH2:7][OH:8])[CH2:2][CH2:3][CH3:4].[O:14]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]1[C:16]([O:18][CH3:19])=[O:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:14][CH:15]([C:20]([O:8][CH2:7][C:6](=[O:9])[N:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCN(CCCC)C(=O)CO
Reactant: COC(=O)C1OC1(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)COC(c1ccccc1)(c1ccccc1)C(O)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
1.3 g of N,N-di-n-butyl-2-hydroxyacetamide and 1.8 g of methyl 2,3-epoxy-3,3-diphenylpropionate were dissolved in 30 ml of methylene chloride and, while cooling in ice, a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred at room temperature for 24 hours and then added to sodium bicarbonate solution, the organic phase was separated off and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by chromatography, and 1.4 g of an oil were isolated and were immediately reacted further.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>[N+](C)([O-])=O>[CH:14]([C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH3:6])=[CH:8][CH:9]=1)=[O:17])([CH3:16])[CH3:15]
Reactant: CCc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCc1ccc(C(=O)C(C)C)cc1
Yield: 77 %

Procedure:
At 10° C. a solution of 93 g (0.72 mol) AlCl3 in 250 ml nitromethane is added to a mixture of 66 g (0.62 mol) ethyl benzene and 70 g (0.66 mol) isobutyroyl chloride, after which the mixture is stirred during half an hour. The reaction mixture is poured out into ice and extracted with ether. The solution in ether is washed neutral, dried on MgSO4 and evaporated. The residue is distilled under diminished pressure to obtain p-ethylphenyl isopropyl ketone in a yield of 77%.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]2>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:26]=[C:25]2[C:21](=[CH:20][CH:19]=1)[CH2:22][CH:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]2
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Br)cc2C1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C2
Yield: 15 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.1 g, 3.6 mmol) was reacted with tert-butyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate (2.0 g, 5.6 mmol) to afford the desired product (250 mg, 15%) as a brown solid: ESI MS m/z 363 [C26H26N2O4S+H-100]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[CH3:56][O:57][C:58](=[O:76])[C:59]1[CH:64]=[CH:63][C:62](/[CH:65]=[CH:66]/[C@@H:67]([NH2:75])[CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)=[CH:61][CH:60]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:75][C@H:67](/[CH:66]=[CH:65]/[C:62]1[CH:61]=[CH:60][C:59]([C:58]([O:57][CH3:56])=[O:76])=[CH:64][CH:63]=1)[CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(/C=C/[C@@H](N)Cc2ccccc2)cc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccc(C(=O)OC)cc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-3-{[(2S,3E)-4-[4-(methoxycarbonyl)phenyl]-1-phenylbut-3-en-2-yl}amino)-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 12.7 mg (32 μmol) methyl-4-[(1E,3S)-3-amino-4-phenylbut-1-en-1-yl]benzoate trifluoroacetic acid salt (intermediate 16).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:25])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][N:35]([CH:43]([CH3:45])[CH3:44])[C:34]2=[O:46])=[CH:29][CH:28]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:25][C:40]([C:37]3[C:38](=[O:39])[N:33]([C:30]4[CH:29]=[CH:28][C:27]([F:26])=[CH:32][CH:31]=4)[C:34](=[O:46])[N:35]([CH:43]([CH3:45])[CH3:44])[CH:36]=3)=[O:41])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C3CC3)c2cc1OC
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C3CC3)c2cc1OC

Procedure:
This compound was synthesized from 3-cyclopropyl-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (0.06 g, 0.20 mmol) and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.063 g, 0.21 mmol) in an analogous manner to Example 59. mp 172-174° C.; LCMS m/z=611 (M+1). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), 8.67 (s, 1H), 8.44 (d, 1H, J=5.24 Hz), 7.65 (dd, 1H, J=2.52 Hz, J=7.65 Hz), 7.58 (s, 1H), 7.31-7.48 (m, 6H), 7.16 (d, 1H, J=8.73 Hz), 6.34 (d, 1H, J=5.20 Hz), 4.70-4.85 (m, 1H), 3.94 (s, 6H), 1.78-1.88 (m, 1H), 0.73-0.82 (m, 2H), 0.62-0.69 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1([CH:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[CH2:32][CH2:31][N:30]2[CH3:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1([CH:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:37]=3)[CH2:32][CH2:31][N:30]2[CH3:42])[CH2:28][CH2:27]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)Oc1cc2c(cc1OC)CCN(C)C2C1(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hexadecanoyl chloride (0.83 g) in dichloromethane (5 ml) was added dropwise to a stirring solution of 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.04 g, prepared from the (+)-enantiomer of the hydrobromide salt, prepared in a similar manner to that described in Example 77), triethylamine (0.91 g) and dichloromethane (20 ml). The mixture was stirred at ambient temperature for 2 hours, then washed with dilute sodium hydroxide solution, water and brine. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting oil was dissolved in petroleum ether (b.p. 60°-80° C.) and washed repeatedly with water. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinoline (1.45 g) which had a specific optical rotation αD of +21.18°.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH2:42]([NH:49][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:20][CH:19]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCc1ccccc1)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 40 mL scintillation vial containing 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid (150 mg, 0.55 mmol, 1.0 eq.), EDCI (157.2 mg, 0.82 mmol, 1.5 eq.), HOBt (111.5 mg, 0.82 mmol, 1.5 eq.) and DMAP (12 mg, 0.1 mmol, 0.2 eq.) in DCM (10.0 mL) was added benzylamine (24 μL, 2.2 mmol, 4.0 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was treated with H2O (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×5 mL), combined organic phase was washed with brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-benzyl-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzamide as a white solid. LCMS (m/z) 360 (M+H); 1H NMR (DMSO-d6) δ: 9.01 (t, J=6.0 Hz, 1H), 7.91-8.00 (m, 2H), 7.76 (d, J=7.9 Hz, 1H), 7.29-7.36 (m, 5H), 7.21-7.27 (m, 1H), 7.08-7.13 (m, 2H), 7.02-7.07 (m, 2H), 4.95 (s, 2H), 4.48 (d, J=6.0 Hz, 2H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[N:16]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:15]=[CH:14][CH:13]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[CH:17]1([N:16]2[C:12]([NH:11][C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]([OH:6])=[O:5])=[CH:13][CH:14]=[N:15]2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: Nc1ccnn1C1CCCC1
Reactant: O=C(O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1Nc1ccnn1C1CCCC1
Temperature: 0 °C
Yield: 68.5 %

Procedure:
A mixture of 2-iodobenzoic acid (28 g, 0.113 mol), 5-amino-1-cyclopentylpyrazole (17 g, 0.113 mol), DMF (100 ml), potassium carbonate (16 g, 0.113 mol) and Cu(OAc) 2 (0.5 g) was refluxed overnight. The reaction mixture was poured into ice-water, and acidified with acetic acid to a pH of 5. The gum which formed was extracted with CH2Cl2 and the CH2Cl2 layer was washed with water, dried over MgSO4, and evaporated to afford 21 g of N-(1-cyclopentyl pyrazol-5-yl) anthranilic acid.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]\1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[N:23]1([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[NH:37])=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:38]=[C:36]([NH:35][C:32]3[CH:31]=[CH:30][C:29]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:34][CH:33]=3)[N:37]=[CH:4][C:5]=2[CH2:14]1
Reactant: N=C(N)Nc1ccc(N2CCNCC2)cc1
Reactant: CN(C)/C=C1/C[C@@H](c2ccccc2F)c2ccccc2C1=O
Product: Fc1ccccc1[C@@H]1Cc2cnc(Nc3ccc(N4CCNCC4)cc3)nc2-c2ccccc21

Procedure:
This was synthesized by using (R,Z)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and 1-(4-(piperazin-1-yl)phenyl)guanidine as described in general procedure 1. LCMS m/e 452 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[OH:15].Br[CH2:17][CH2:18][OH:19]>CN(C=O)C.CCOC(C)=O>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:17][CH2:18][OH:19]
Reactant: OCCBr
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCOc1ccc(F)cc1F
Temperature: 120 °C
Yield: 63 %

Procedure:
K2CO3 (1.07 g, 7.78 mmol) was added to a solution of 2,4-difluoro phenol (0.84 g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.81 g, 6.48 mmol) was added, and the mixture was heated overnight at 120° C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4×20 ml), dried over MgSO4, and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 63% yield
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].[CH3:25][Si](C)(C)N[Si](C)(C)C.[Na].CI>C1COCC1>[CH3:25][C:3]1([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][N:2]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)C1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
Step-2: To a solution of 2-benzyl 3-methyl 3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (3 g, 9.23 mmol) in THF (30 mL) at −80° C. was added sodium hexamethyldisilazane (1M, 23.1 mL, 23.1 mmol) and stirred for 20 min. Methyl iodide (1.44 mL, 23.1 mmol) was added and the reaction was allowed to warm to −20° C. and stirred at −20° C. for 6 h. The reaction was quenched with water, neutralized with 2N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford 2-benzyl 3-methyl 3-methyl-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate. MS (ES+): m/z 340.20 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.[H][H].Cl>CO.O.[Pt](=O)=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2nc(-c3cccc(-c4ccncc4)c3)oc12
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1cccc2nc(-c3cccc(C4CCNCC4)c3)oc12
Yield: 21.3 %

Procedure:
2-(3-(Pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide (110 mg, 0.35 mmol) and platinum (IV) oxide monohydrate in methanol was purged with 20 atm of hydrogen at 50° C. for 24 h. Then the mixture was filtered and adjusted to pH=9. The solvent was removed in vacuum. The crude was purified by chromatography (dichloromethane:methanol=9:1) to give the solid. The solid was acidified by hydrochloride acid. 24 mg 2-(3-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained, yield: 21%. 1HNMR (400 MHz, DMSO-d6): δ 1.96 (m, 5H), 3.03 (m, 4H), 7.51 (m, 2H), 7.62 (t, 1H), 7.81 (d, J=6.4 Hz, 1H), 7.83 (brs, 1H), 7.94 (brs, 1H), 7.97 (d, J=6.4 Hz, 1H), 8.14 (s, 1H), 8.19 (d, J=6.4 Hz, 1H), 8.85 (brs, 1H), 9.02 (brs, 1H). LC-MS (ESI) m/z: 322 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH2:12][C:13]([OH:15])=[O:14])([CH3:11])[CH2:8][CH2:7]2.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:14][C:13](=[O:15])[CH2:12][C:9]1([CH3:11])[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:16][CH3:17])[C:2]=2[F:1])[CH2:7][CH2:8]1
Reactant: COc1ccc2c(c1F)C(C)(CC(=O)O)CC2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(C)CCc2ccc(OC)c(F)c21
Reaction time: 4 h

Procedure:
The racemic carboxylic acid 38.4 (180 mg, 0.77 mmol) was dissolved in MeOH (40 mL) and a catalytic amount of concentrated sulfuric acid was added. The solution was heated to reflux and stirred for 4 hours. The reaction was concentrated under reduced pressure and diluted with EtOAc, washed with water, and washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate to give the racemic (7-fluoro-6-methoxy-1-methyl-indan-1-yl)-acetic acid methyl ester (194 mg, 0.77 mmol). The racemic methyl ester was subsequently dissolved in dichloroethane (8.0 mL) and cooled to 0° C. To the solution was added ethanethiol (0.17 mL, 2.4 mmol) followed by aluminum chloride (310 mg, 2.3 mmol). The reaction mixture was then warmed to room temperature and stirred for one hour. The reaction was diluted with DCM (300 mL) and washed with saturated sodium bicarbonate solution (200 mL). The aqueous layer was extracted with DCM (3×300 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was then passed through a plug of silica using an EtOAc:DCM mixture to give racemic 7-fluoro-6-hydroxy-1-methyl-indan-1-yl)-acetic acid methyl ester (170 mg, 93%). The racemic material was then purified by chiral HPLC (column: AD; solvent: 5% IPA/hexane) to yield 38.5 (64 mg, 38%) (retention time 30 minutes) and 38.6 (61 mg, 36%) (retention time 55 minutes). One of either 38.5 or 38.6 has the R stereochemistry at the β carbon and the other has the S stereochemistry at the β carbon. MS ESI (pos.) m/e: 239.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.75-6.87 (m, 2H), 5.20 (br. s., 1H), 3.64 (s, 3H), 2.87 (t, J=7.2 Hz, 2H), 2.66-2.84 (m, 2H), 2.33 (dt, J=12.9 Hz, 7.4 Hz, 1H), 1.99 (dt, J=13.0 Hz, 7.4 Hz, 1H), 1.46 (s, 3H).