Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH3:28]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:26][CH2:25][O:24][CH3:23])[CH3:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNCCOC
Product: COCCN(C)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and N-(2-methoxyethyl)methylamine were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-(2-methoxy-ethyl)-methyl-amine, MS: 450 (MH+, 1Br).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([F:48])[CH:42]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:17]1)=[O:6])=[N+]=[N-].[H][H]>CO.[Pd]>[NH2:1][C@@H:4]([C@@H:40]([C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][CH:50]=1)[C:41]1[CH:42]=[C:43]([F:48])[CH:44]=[C:45]([F:47])[CH:46]=1)[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:39])[C:13]=1[CH2:14][CH2:15][C@H:16]1[O:21][CH2:20][C@H:19]([CH2:22][O:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:29])[F:30])=[O:25])[N:18]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:17]1)=[O:6]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N)[C@@H](c2ccc(F)cc2)c2cc(F)cc(F)c2)OC[C@@H]1COC(=O)NCC(F)(F)F

Procedure:
A solution of (2S,3S)-2-azido-3-(4-fluorophenyl)-3-(3,5-difluorophenyl)-N-(5-fluoro-4-(2-((2R,5R)-4-(tert-butyloxycarbonyl)-5-(2,2,2-trifluoroethylaminocarbonyloxymethyl)morpholine-2-yl)ethyl)pyridin-3-yl)propanamide (36 mg, 0.046 mmol) in 1 mL of MeOH was purged with nitrogen gas for 1 min. To the solution was added 10% palladium on carbon (18 mg) and the mixture was stirred under 1 atmosphere of hydrogen gas for 4 h. The catalyst was removed by filtration and the filtrate solvents were removed in vacuo to give a gum. LC MS: RT=1.20 min, M+H=758 (2 min gradient)
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].NC[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1.C1(O)C=CC=CC=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][CH2:24][C:25]4[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CCN(CC)C(=O)c1ccc(CCN)cc1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: Oc1ccccc1
Product: CCN(CC)C(=O)c1ccc(CCn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.310 mmol), 4-(2-amino-ethyl)-N,N-diethyl-benzamide (0.082 g, 0.372 mmol) and phenol (1.0 g) were stirred at 135° C. for 2 hours. The reaction mixture was allowed to cool to r.t. and the product precipitated by the addition of MeOH (16 mL). The precipitate was filtered off and washed with MeOH to give the title compound. Yield: 0.058 g (40%). 1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.61 (d, 2H, J=8.67 Hz), 7.39-7.44 (m, 3H), 7.30 (d, 2H, J=8.19 Hz), 7.18 (d, 2H, J=8.19 Hz), 4.23 (t, 2H, J=7.05 Hz), 3.51 (bs, 1H), 3.46 (d, 2H, J=5.39 Hz), 3.21 (bs, 1H), 3.12 (t, 2H, J=6.64 Hz), 1.21 (bs, 3H), 1.08 (bs, 3H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6](OC)=[O:7].[NH3:29]>C(O)CO>[NH:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:29][C:6](=[O:7])[C:5]2=[CH:10][C:11]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccccc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: O=C1NC(=O)c2cc(Nc3ccccc3)c(Nc3ccccc3)cc21
Reaction time: 24 h

Procedure:
A suspension of 230 mg (0.7 mmol) of 4,5-bis(anilino)phthalic acid dimethylester in 23 ml of ethylene glycol is heated at 120°; ammonia gas is passed through the suspension, with stirring, for 24 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with dichloromethane/methanol 40:1 and the product fractions arecombined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, m.p. 215°-217°, FAB-MS: 330 [M+ +H].
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[N:24]=C(Cl)[C:22]([F:26])=[CH:21][N:20]=1.C(#[N:29])C>C(OCC)(=O)C>[Cl:18][C:19]1[N:24]=[C:3]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([CH3:1])=[N:29]2)[C:22]([F:26])=[CH:21][N:20]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1c[nH]cc1C
Reactant: CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2nc(Cl)ncc2F)nc1C
Temperature: 80 °C
Yield: 85 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrrole-4-carboxylate (3.15 g, 20.5 mmol) in acetonitrile (MeCN) were added potassium carbonate (5.7 g, 41 mmol) and 2,4-dichloro-5-fluoropyrimidine (3.4 g, 20.5 mmol) at room temperature. The resulting slurry was heated at 80° C. for 3 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then partially concentrated in vacuo. To this, n-hexanes were added to form pale yellow precipitates. The resulting solids were collected by filtration and rinsed with n-hexanes and then dried under high vacuum to give 4.9 g (85%) of the target intermediate 3; MS (ESI) m/z 285 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]([CH2:11]Cl)([CH3:10])[CH2:4][CH:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[Li]CCCC.[C-:18]1[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[PH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.[Li+].[CH:32]1[CH:37]=[CH:36][C:35]([P-:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.[K+]>C1COCC1.O>[CH:5]1([CH2:4][C:3]([CH2:2][P:23]2[C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[C:26]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]2=3)([CH2:11][P:38]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6]1
Reactant: CC(CCl)(CBr)CC1C=CC=C1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: [c-]1cccc2[pH]c3ccccc3c12
Agent: [K+]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(CC1C=CC=C1)(CP(c1ccccc1)c1ccccc1)Cp1c2ccccc2c2ccccc21

Procedure:
In a 250 ml Schlenk tube fitted with a septum, 1.58 g (6.31 mmol) of 12 were dissolved in 50 ml of THF, deprotonated at 0° C. by addition of 2.75 ml of n-BuLi solution and stirred further for half an hour. Via a capillary hose, one equivalent of a lithium dibenzophospholide solution was added dropwise at 0° C. over a period of half an hour. The yellow-orange reaction mixture was stirred for another 2 hours at this temperature and subsequently evaporated to about 30 ml in an oil pump vacuum. At room temperature, the reaction solution was then added to 3.5 equivalents of a potassium diphenylphosphide solution over a period of 1 minute and the mixture was stirred for 16 hours at room temperature. The solvent was subsequently substantially removed in an oil pump vacuum and the residue was taken up in 50 ml of diethyl ether. Hydrolysis was carried out by adding 20 ml of water and stirring for 10 minutes. The organic phase was separated off and the aqueous phase was extracted twice with 30 ml of diethyl ether. The combined ether phases were washed with sodium chloride solution until neutral and dried over sodium sulfate. The solvent was removed in an oil pump vacuum, the residue was dissolved in methylene chloride and absorbed on kieselguhr. This was followed by flash chromatography on silica gel (20*4 cm; eluant: PE/diethyl ether in a ratio of 9.75:0.25; RF =0.31). This gave 0.7 g (22%) of 5d as a colorless, viscous oil.
Reaction SMILES: [Na].[C:2]1([C:8]2[C:9]([CH:27]=[CH2:28])=[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([B:14])[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][C:31]1[NH:32][CH:33]=[CH:34][N:35]=1>CC(C)=O>[C:2]1([C:8]2[C:9]([CH:27]=[CH2:28])=[C:10]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([B:14])[CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[NH:35][CH:34]=[CH:33][NH+:32]=1
Reactant: Cc1ncc[nH]1
Agent: Cl
Agent: [B]c1cc(-c2ccccc2)c(C=C)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na]
Solvent: CC(C)=O
Product: Cc1[nH]cc[nH+]1

Procedure:
Triphenyl-(4-vinyl)phenylboron sodium (0.05 moles) was reacted with 2-methylimidazole hydrochloride (0.05 moles) in the similar manner to that of Example 4 using acetone as the reaction solvent to give 20.0 g (yield: 93.7%) of the titled compound as colorless crystal. M.p. 234° to 236° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17](=[O:36])[NH:18][C:19]3[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[C:20]=3[O:34][CH3:35])[CH:14]=[CH:13][C:12]=2[CH3:37])[CH:10]=1)=[O:5])C.O[Li].O.CC(O)=O>CO.O>[C:25]([C:23]1[CH:22]=[C:21]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])[C:20]([O:34][CH3:35])=[C:19]([NH:18][C:17]([C:15]2[CH:14]=[CH:13][C:12]([CH3:37])=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=2)=[O:36])[CH:24]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CCOC(=O)c1cn(-c2cc(C(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)ccc2C)cn1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cnc(C(=O)O)c3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.3 %

Procedure:
1-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-imidazole-4-carboxylic acid ethyl ester (Example 3) (820 mg, 1.55 mmol) was dissolved in 5 mL of cold MeOH and a solution of 130 mg (3.10 mmol) of LiOH-H2O in 3 mL of water was added dropwise. The mixture was allowed to warm to room temperature and was then stirred for 4 h. A 1 N HOAc solution (3.2 mL) was then added and the mixture was diluted with 30 mL of water, and then was extracted with 75 mL of EtOAc. The extract was washed with water and brine, was dried with MgSO4, filtered, and concentrated to provide 631 mg (1.26 mmol, 81%) of 1-[5-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-2-methyl-phenyl]-1H-imidazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: Clc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: Oc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(Cl)cc23)CC1

Procedure:
A mixture of 3.1 g of 4,6-dichloro-2-(4-chlorophenyl)quinoline, 2.56 g (20 mmol) of isonipecotamide, and 10 g of phenol was stirred and heated in an oil bath at 160°-170° for 4 hr. It was then cooled and diluted with water. It was made alkaline with 3N sodium hydroxide, and crystallization was induced by the addition of ether and scratching. The solid was collected and washed with ether to give 2.45 g of crude product. Recrystallization from ethanol gave the above-named compound as off-white prisms, mp 272°-275°.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:29]/[CH:30]=[CH:31]/[CH:32]=[CH:33]/C=O)[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCC[CH2:37]1>>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:28]=[CH:29]/[CH:30]=[CH:31]/[CH:32]=[CH:33]/[CH:5]=[CH:4]/[C:6]([O:8][CH3:37])=[O:7])[CH:23]=[CH:24][C:25]=2[O:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: COc1ccc(/C=C/C=C/C=C/C=O)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/C=C/C=C/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 2 h

Procedure:
To a stirred suspension of 0.13 g (2.71 mmol) of a 50% oil suspension of sodium hydride (previously washed with three, 3 mL portions of hexane) in 50 mL of dry tetrahydrofuran under a nitrogen atmosphere was added dropwise at room temperature 0.33 mL (2.04 mmol) of trimethylphosphonoacetate in 20 mL of dry tetrahydrofuran over a 5 minute period. The white suspension was stirred for an additional 2 hours after which time 0.40 g (1.34 mmol) of 7-(3-cyclopentoxy-4-methoxyphenyl)-2,4,6-E,E,E-heptatriene-1-aldehyde in 20 mL of dry tetrahydrofuran was added dropwise over a 5 minute period. The final reaction mixture was stirred for an additional 2 hours after which time the mixture was quenched with 50 mL of saturated sodium chloride. The mixture was extracted with three, 50 mL portions of ethyl acetate and the combined organic fractions were washed with 50 mL of saturated sodium chloride, dried over sodium sulfate and concentrated. Liquid chromatography of the crude product over 100 g of silica gel eluting with 10% ethyl acetate in hexane provided the desired, analytically pure yellow oil.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[NH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([Cl:33])[CH:28]=1)N>>[Cl:33][C:29]1[CH:28]=[C:27]([N:25]2[C:17]([C:12]3[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=4)[N:11]=3)=[CH:18][CH:19]=[N:20]2)[CH:32]=[CH:31][N:30]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccnc(Cl)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 4-hydrazino-2-chloropyridine according to the method described for example 91. MS: M=416.1 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:20]([C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([O:37][Si](C)(C)C)=[C:29]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O>CO>[C:16]([C:9]1[CH:8]=[C:7]([P:20]([C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([OH:37])=[C:29]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[OH:11])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1cc(P(c2ccccc2)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(P(c2ccccc2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Yield: 38.6 %

Procedure:
A solution of 1.0 g (1.5 mmol) of bis(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)phenylphosphine and 2.0 g of water in 25 ml of methanol is heated at reflux temperature for 4 hours. The solvent is removed in vacuo and the residue purified by flash chromatography (silica gel, 9:1 heptane:ethyl/acetate eluent) to give 0.3 g (34%) of a white solid, m.p. 138°-140° C.
Reaction SMILES: C1([C@H](NCC2C=CC=C(C(C)(C)C)C=2O)[C@@H](NCC2C=CC=C(C(C)(C)C)C=2[OH:27])C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zr+4]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:27])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: CC(C)(C)c1cccc(CN[C@@H](c2ccccc2)[C@@H](NCc2cccc(C(C)(C)C)c2O)c2ccccc2)c1O
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: [Zr+4]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)(C)OO
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 65 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
A chiral zirconium complex was prepared by rapidly stirring (forming a vortex) a mixture of zirconium(IV) acetylacetonate (43.5 mg, 0.089 mmol) and 2,2′-[[(1S,2S)-1,2-diphenyl-1,2-ethanediyl]bis(iminomethylene)]bis[6-(1,1-dimethylethyl)-phenol] (Formula Mb wherein R6 is H, 0.096 g, 0.18 mmol) in toluene (1.00 mL) at 50° C. for one hour. The resulting solution was evaporated to dryness in vacuo, then a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) in toluene (2.00 mL) was added. The reaction mixture was heated to 65° C., and then an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 0.340 mL, 2.46 mmol) was added. After 3.5 hours at 65° C., the reaction was quenched by adding an acetonitrile solution (7.00 mL) containing biphenyl (0.125 g) as an HPLC internal standard and cooling to ambient temperature. Analysis by quantitative and chiral HPLC showed 100% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 85% yield (85% chemoselectivity) and 94% enantiomeric excess of the S-enantiomer.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1.CO>C1COCC1>[Br:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(Br)cc2)c2ncccc2Cl)C1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
Preparation 1 tert-Butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (214.4 g, 687.7 mmol) was dissolved in 260 mL of THF and the resulting suspension was cooled to −10° C. Lithium bis(trimethylsilyl)amide (1 mol/L in THF, 687.7 mL, 687.1 mmol) was added over 25 min followed by warming to 20° C. and stirring for 1 h before cooling back to −10° C. 4-Bromobenzoyl chloride (140.0 g, 625.2 mmol) was added as a solution in 230 mL of THF over 1.5 h, maintaining the internal temperature at less than −7° C. After complete addition, the reaction mixture was warmed to 0° C. at which point HPLC indicated the reaction was complete. MeOH was added (101 mL), then the reaction was warmed to room temperature and concentrated in vacuo to a low volume. The solvent was then exchanged to 2-MeTHF. The crude product solution (700 mL in 2-MeTHF) was washed with 700 mL of half-saturated aqueous NaHCO3, followed by 200 mL of half-saturated brine. The 2-MeTHF solution was concentrated to a low volume followed by addition of 400 mL of heptane resulting in precipitation of solids which were collected via filtration. The collected solids were dried to afford the title compound as a tan powder (244 g, 79% yield).
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH2:16][CH3:17])[C:4]1=[O:18])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:32]([O-])([O-:34])=[O:33].[K+].[OH-].[Na+]>CC#N.O>[CH2:1]([CH:3]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[C:12]([N+:32]([O-:34])=[O:33])=[CH:13][C:8]=2[CH2:7][CH2:6][N:5]([CH2:16][CH3:17])[C:4]1=[O:18])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCC1C(=O)N(CC)CCc2ccc(OC)cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCC1C(=O)N(CC)CCc2cc([N+](=O)[O-])c(OC)cc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 30.8 %

Procedure:
1,3-Diethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (564 mg, 2.28 mmol) was dissolved in 1 ml of anhydrous MeCN. The reaction was cooled to 0° C. and trifluoroacetic anhydride (3.00 mL, 21.2 mmol) and Potassium nitrate (230 mg, 2.28 mmol) were charged. The reaction was stirred for 1.5 h and then the reaction was basified with 1-2 ml of 30% NaOH solution and allowed to stir for 1 h. Pour reaction into 75 ml water and extract with 3×30 ml portions of methylene chloride. Dry the combined organic over magnesium sulfate and evaporate. Product is a yellow brown oil (625 mg). Crude material was chromatographed on a 40 g Isco column using 30-50% EtOAc in hexanes as the eluent to yield 1,3-diethyl-8-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[d]azepin-2-one (205 mg, 31%) as a tan waxy solid as a mixture of diastereomers. 1H-NMR (CDCl3) δ 7.65 (s, 1H), 6.85 (s, 1H), 4.09-3.90 (m, 5H), 3.60-3.35 (m, 3H), 3.30-3.04 (m, 2H), 2.25 (p, J=7 Hz, 1H), 1.86 (p, J=7 Hz, 1H), 1.15-1.00 (m, 6H). LC/MS (ESI+): 293 (M+H)
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5]([F:10])[CH2:4]1.[CH:18]1[CH:19]=[CH:20][C:21]2[NH:26][CH:25]=[C:24]([CH2:27][CH2:28]O)[C:22]=2[CH:23]=1.O([Si](C)(C)C)S(C(F)(F)[F:35])(=O)=O.[OH-].[Na+]>ClCCl>[F:10][CH:5]1[C:6]2([C:25]3[NH:26][C:21]4[C:22]([C:24]=3[CH2:27][CH2:28][O:9]2)=[CH:23][C:18]([F:35])=[CH:19][CH:20]=4)[CH2:7][CH2:8][C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([N:2]([CH3:17])[CH3:1])[CH2:4]1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C1(c2ccccc2)CCC(=O)C(F)C1
Reactant: OCCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(OCCc3c2[nH]c2ccc(F)cc32)C(F)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The more polar 4-dimethylamino-2-fluoro-4-phenylcyclohexanone (950 mg, 4.04 mmol) together with tryptophol (723 mg, 4.04 mmol) was dissolved in absolute dichloromethane (45 ml) at 0° C. (inside temperature). Trimethylsilyl triflate (987 mg, 4.44 mmol, 0.81 ml, 1.225 g/ml) was then added quickly in drops to absolute dichloromethane (10 ml). The reaction mixture immediately changed colour from yellow to red-brown. The reaction mixture was stirred for 5 h at room temperature and became cloudy during this. 5N sodium hydroxide solution (60 ml) was added to the reaction mixture and stirred for 10 min. A colourless solid separated out of the two-phase mixture. This was filtered off by means of a fritted glass filter and then washed with methanol (50 ml). The solid was the more polar diastereoisomer (241 mg). The more polar diastereoisomer was separated from the filtrate again and filtered off once again. After phase separation the aqueous phase was extracted with dichloromethane (4×40 ml). The combined organic phases were dried over sodium sulphate, filtered and then completely freed of volatile constituents in a vacuum. An attempt was made to separate the residue by chromatography [silica gel (150 g), chloroform/ethanol 19:1 (1000 ml), methanol (500 ml)]. 676 mg (1.70 mmol, 42%, mp 260-265° C.) of a more non-polar diastereomer and a total of 572 mg (1.44 mmol, 36%, mp 237-242° C.) of the more polar diastereoisomer were isolated.