Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](/[CH:57]=[CH:58]/[CH2:59][C:60]([OH:62])=[O:61])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([O:70][CH2:71][CH2:72]O)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](/[CH:57]=[CH:58]/[CH2:59][C:60]([O:62][CH2:72][CH2:71][O:70][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)=[O:61])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(/C=C/CC(=O)O)cc3)c12
Reactant: OCCOCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(/C=C/CC(=O)OCCOCc4ccccc4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To a mixture of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-[4-((1E)-3-carboxyprop-1-enyl)benzyl]-7-methyl-1H-indole (0.10 g), 2-(benzyloxy)ethanol (22 mg), 4-dimethylaminopyridine (7 mg) and dichloromethane (0.5 mL) was added dicyclohexylcarbodiimide (37 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was directly purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=4/1-2/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-{(1E)-3-[2-(benzyl-oxy)ethoxycarbonyl]prop-1-enyl}benzyl)-7-methyl-1H-indole (48 mg). This material was dissolved in a mixed solvent of methanol (1 mL) and tetra hydrofuran (1 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=12/1-8/1) to give the title compound (14 mg).
Reaction SMILES: Cl.[CH3:2][C@@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl>[Cl:19][C:17]1[CH:16]=[C:15]([S:20]([N:4]2[CH2:5][CH2:6][CH2:7][C@@:3]2([CH3:2])[C:8]([O:10][CH3:11])=[O:9])(=[O:21])=[O:22])[CH:14]=[C:13]([Cl:12])[CH:18]=1
Reactant: COC(=O)[C@]1(C)CCCN1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)[C@]1(C)CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
2-methyl-(L)-proline, methyl ester hydrochloride (95 gm, 52.9 mmol) was dissolved in a mixture (1:1) of dry THF and CH2Cl2 (250 mL). A solution of 3,5-dichlorobenzenesulfonyl chloride (13.0 gm, 52.9 mmol) in dry CH2Cl2 (20 mL) was added. The reaction was cooled in an ice bath and diisopropylethylamine (20.5 gm, 158.6 mmol) was added. The ice bath was removed and the reaction mixture was stirred overnight at rt. The reaction was concentrated and dried to a tan solid (18.68 gm). This solid was purified on a Biotage 40M chromatography system eluted with 10% EtOAc in hexanes to yield N-(3,5-dichlorobenzenesulfonyl)-2-methyl-(L)-proline, methyl ester as a pure white solid (16.8 gm, 85% yield).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16](=[O:31])[NH:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:29][C:27]([F:28])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([C:20]#[C:19][CH2:18][NH:17][C:16]([CH2:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:32])=[O:3])=[CH:10][CH:11]=2)=[O:31])=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cn1ccc2ccc(CC(=O)NCC#Cc3ccc(C(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(CC(=O)NCC#Cc3ccc(C(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 e], (6-{[3-(4-trifluoromethyl-phenyl)-prop-2-ynylcarbamoyl]-methyl}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain the title compound as off-white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[H][H]>[Pd].CCOC(C)=O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)CC1
Yield: 92.5 %

Procedure:
6.7 g of 4,4-dimethyl-2-cyclohexen-1-one and 2 g of 10% Pd/C are added to 65 ml of EtOAc and the mixture is hydrogenated at RT under atmospheric pressure until the theoretical volume of hydrogen has been absorbed. The catalyst is filtered off and the filtrate is then concentrated to give 6.3 g of the expected product.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[ClH:18].[NH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(O)(C)C>[ClH:18].[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)[CH2:17][NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COC(=O)CCc1ccc(OCC2CO2)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNCC(O)COc1ccc(CCC(=O)OC)cc1

Procedure:
A mixture of 5 gm (0.02 mole of methyl 3-[4-(2,3-epoxypropoxy)phenyl]propionate, 3 gm (0.02 mole) of ethyl 3-aminopropionate hydrochloride and 2.8 ml (0.02 mole) of triethylamine in25 mL of isopropanol was heated to reflux for 4 hours. The reaction medium was then cooled and the triethylamine hydrochloride side-product which crystallized was removed by filtration. The mother liquor was then evaporated under reduced pressure and the resulting residue taken up in ethanol and treated with ethereal HCl to provide 1 gm (12%) as a crystalline solid: mp 110°-111°. The NMR spectrum was consistent with the assigned structure and the elemental analysis was consistent with the formula C18H28NO6Cl.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[C:4]#[C:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)C=O.O>[CH2:21]([N:2]([CH3:1])[C:3](=[O:18])[C:4]#[C:5][C:6]1[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=1)[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CNC(=O)C#Cc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#CC(=O)N(C)CC=Cc2ccccc2)cc(OC)c1OC
Reaction time: 15 h

Procedure:
The solution of 10.0 g of N-methyl-3,4,5-trimethoxyphenylpropiolamide in 80 ml of dimethylformamide is added dropwise to the suspension of 1.05 g of sodium hydride in 10 ml of dimethylformamide while stirring and cooling with ice. The mixture is stirred for 1 hour at room temperature whereupon the solution of 8.0 g of cinnamyl bromide in 40 ml of dimethylformamide is added dropwise and stirring is continued for 15 hours at room temperature. The mixture is poured into the solution of 20 ml of 3N hydrochloric acid in 600 ml of water and the whole is extracted with 250 ml of toluene. The extract is washed with 2N aqueous sodium hydroxide and saturated aqueous sodium chloride, dried and filtered, to yield the desired toluene-solution of the N-cinnamyl-N-methyl-3,4,5-trimethoxyphenylpropiolamide.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1

Procedure:
48.4 g of ethyl 2-chloro-5-ureido-benzoate and 31.2 g of ethyl cyclopentanone-2-carboxylate are heated under reflux for 6 hours in 500 ml of benzene and 2 g of toluene-4-sulphonic acid monohydrate. The water formed is removed by means of a water separator. The reaction mixture is subsequently evaporated to dryness, the residue is dissolved in 700 ml of diethyl ether and the solution is filtered. The filtrate is evaporated to dryness and the residue is purified by chromatography on 1.5 g of silica gel using diethyl ether/n-hexane (1:2) as the eluent. This is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-cyclopenten-1-yl]ureido}-benzoate as colourless crystals. The product is recrystallized from diethyl ether/n-hexane, m.p. 110°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:6].Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:6]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C(C)Oc1ccc(-c2ccc(CCNC(=O)c3cc(Cl)ccc3OC)cc2)cc1
Yield: 26 %

Procedure:
Ethyl 2-{4-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(2-methoxy-5-chlorobenzamido)-ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-propionate analogous to Example 1. Yield: 26% of theory; m.p. <20° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[N:13]([CH2:14][C:15]([OH:17])=O)[C:12](=[O:18])[CH2:11]2)=[CH:5][CH:4]=1.[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([NH:26][C:15](=[O:17])[CH2:14][N:13]1[CH:10]([S:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][C:12]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(SC2CC(=O)N2CC(=O)O)cc1
Reactant: NCc1ccccc1
Product: COc1ccc(SC2CC(=O)N2CC(=O)NCc2ccccc2)cc1
Yield: 74 %

Procedure:
Treatment of (4-(4-methoxyphenylthio)-2-oxoazetidin-1yl)acetic acid with benzylamine under the conditions described in Example 86 gave the title compound as a colourless oil, 74% yield. 1H NMR δ (CDCl3) 2.80, 2.86 (1H, dd, J=2.3, 15.2 Hz, H3), 3.29, 3.35 (1H, dd, J=5, 15.2 Hz, H3), 3.79 (3H, s, OCH3), 3.85, 4.05 (each 1H, d, J=16.7 Hz, NCH2), 4.43 (2H, d, J=5.7 Hz, NHCH2), 4.97 (1H, m, H4) 6.5 (1H, m, NH), 6.83 (2H, d, J=8.6 Hz, 4-OCH3Ph-H), 7.24-7.35 (7H, m, Ph-H, 4-OCH3Ph-H). ν c=o 1775 cm-1. Found: C, 64.0 H, 5.8; N, 8.1%. C19H20N2O3S requires: C, 64.0; H, 5.7 N, 7.9%
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[N:26]=[C:25](Br)[CH:24]=[N:23][C:22]=3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH3:37][N:38]1[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[N:40]=[CH:39]1>CN(C=O)C.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.[Cu]I>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:41]4[N:40]=[CH:39][N:38]([CH3:37])[CH:42]=4)[N:26]=3)[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cnc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
In a pressure tube 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide (125 mg, 0.22 mmol) and 1-methyl-4-tributylstannanyl-1H-imidazole (97 mg, 0.26 mmol) were dissolved in DMF (2 mL). Pd(PPh3)4 (12.5 mg, 0.01 mmol) and CuI (8 mg, 0.04 mmol) were added. The tube was sealed and heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with saturated aqueous LiCl and brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (0-10% MeOH/EtOAc) to afford 121 mg (95%) of 2-(1-methyl-1H-imidazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide as a light brown gum.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH2:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:44]=O)[CH2:40][CH2:39]2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:44][C@H:41]1[CH2:42][CH2:43][C@H:38]([CH2:37][CH2:36][C@H:33]2[CH2:32][CH2:31][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:39][CH2:40]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=C(Br)Br)CC2)CC1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.4 g of tetrabromomethane in 80 ml of methylene chloride was placed at -15° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.0 g of triphenylphosphine in 20 ml of methylene chloride. The clear deep orange solution was stirred at -5° C. for a further 10 minutes and then a solution of 1.95 g of the trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes, then poured into 600 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at 0° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.0 g) on silica gel with hexane gave 2.68 g (89.2%) of trans-1-(2,2-dibromovinyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane which contained about 10% of the corresponding epimeric cis compound in accordance with NMR spectroscopic analysis and which was used without additional purification.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15]>>[Cl:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([C:7]1[CH:6]=[CH:5][C:2]([O:3][CH3:4])=[C:1]([O:9][CH3:10])[CH:8]=1)=[O:15]
Reactant: COc1ccccc1OC
Reactant: CC(C)(CCl)C(=O)Cl
Product: COc1ccc(C(=O)C(C)(C)CCl)cc1OC
Temperature: 70 °C
Yield: 93 %

Procedure:
A 50 mL round bottom flask equipped with a stir bar was charged with veratrole (1.3 mL, 10 mmol) and 3-chloropivaloyl chloride (1.4 g, 10 mmol). To this mixture was added polyphosphoric acid (20 g). The mixture was heated at 70° C. for 2 h. [The progress of the reaction was followed by removing an aliquot for mini workup and NMR analysis.] The material was added to a mixture of ice water (100 mL)/EtOAc (100 mL) and stirred until the polyphosphoric acid had dissolved. The phases were separated and the EtOAc phase was washed with sat. NaHCO3 (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was used as is in the next step. Amount obtained: 2.4 g, 9.3 mmol, 93% yield. LC-MS (ESI) m/e 257 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (s, 6H) 3.83 (s, 2H) 3.93 (s, 3H) 3.95 (s, 3H) 6.87 (d, J=8.44 Hz, 1H) 7.37 (d, J=1.95 Hz, 1H) 7.48 (dd, J=8.42, 1.98 Hz, 1H). Step 2
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([CH:18]=[N:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][NH:24]2)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.Cl[Ti](Cl)(Cl)Cl>[F:14][C:10]1[C:9]([O:15][CH3:16])=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH:18]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]3[C:21]=1[CH:22]=[N:23][NH:24]3)[C:3]([C:2]([F:29])([F:1])[F:30])([OH:17])[CH2:4][C:5]2([CH3:7])[CH3:6]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1c(F)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2[nH]ncc12
Temperature: -22.5 °C
Yield: 81.1 %

Procedure:
1.32 g (3.117 mmol) of the above-described imine, 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-2-[(1H-indazol-4-yl)iminomethyl]-4-methylpentan-2-ol, is dissolved in 22.8 ml of dichloromethane. 9.35 ml of a 1M solution of TiCl4 in dichloromethane (3 equivalents) is added to this solution at −30° C., specifically under nitrogen within 15 minutes. The reaction mixture is stirred for three and one-half hours at −30 to −15° C. The batch is mixed drop by drop with saturated sodium bicarbonate solution at −30° C. After dilution with ethyl acetate, it is stirred for 15 minutes at room temperature. After being extracted twice with 150 ml each of ethyl acetate, the organic phases are washed (water, brine), dried (Na2SO4), and the solvent is spun off. After chromatography on silica gel (mobile solvent:dichloromethane/methanol), 1.07 g (81.1%) of the desired product is obtained as a racemate. The product is separated into its enantiomers (Chiralpak AD 5μ; mobile solvent:hexane/ethanol). The (+)-enantiomer shows an angle of rotation of [α]D=+1.6° (c=1, MeOH), and the (−)-enantiomer shows an angle of rotation of [α]D=−1.3° (c=1, MeOH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].N1C=CN=C1>C1COCC1>[C:20]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:9])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)Cc2ccccc2)cc1
Reaction time: 8 h
Yield: 10.8 %

Procedure:
To a stirring solution consisting of benzyl 4-hydroxyphenyl ketone (650 g) in THF (5.5 L) at room temperature under a nitrogen atmosphere is added tert-butyldimethylsilyl chloride (692 g, 4.59 moles) and imidazole (354 g,). The reaction mixture is stirred overnight and is then concentrated under reduced pressure. The evaporate is dissolved in ether is washed with water and brine, is dried over anhydrous Na2SO4, and is concentrated under reduced pressure to afford a solid. The solid is triturated with pentane. The triturated solids are collected by filtration to afford a solid (850 g.) The filtrate is concentrated under reduced pressure to give a solid. This solid is triturated with pentane and the resulting solids are collected by filtration to provide a second crop of solid (108 g), which afforded a total of 958 g of Compound A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6]2.[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([NH2:13])=[CH:6]2
Reactant: [H][H]
Reactant: COc1ccc2ncc([N+](=O)[O-])cc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(N)cc2c1

Procedure:
A mixture of 6-methoxy-3-nitroquinoline (Magnus, P. et al., J. Am. Chem. Soc. 119, 5591, 1997; 0.17 g, 0.83 mmol) and Pd/C (10%, 80 mg) in EtOAc (15 mL) was hydrogenated with a hydrogen balloon to give 6-methoxyquinolin-3-amine in quantitative yield. LC/MS (m/z): 175.1 (MH+), Rt 1.54 minutes.
Reaction SMILES: [CH3:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:21]=23)[CH:15]=1)([CH2:12][CH3:13])[CH2:3][NH:4]C(=O)OC(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][N:27]=[C:28]([C:29]([F:31])([F:32])[F:30])[C:21]=23)[CH:15]=1)([CH2:12][CH3:13])[CH2:3][NH2:4]
Reactant: CCC(C)(CNC(=O)OC(C)(C)C)c1cccc(-c2ccnc3c2c(C(F)(F)F)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)(CN)c1cccc(-c2ccnc3[nH]nc(C(F)(F)F)c23)c1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 75.7 %

Procedure:
tert-butyl 2-methyl-2-(3-(3-(trifluoromethyl)-1-trityl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)butylcarbamate (148 mg, 0.2142 mmol) was dissolved in dry DCM (2 mL) and cooled in an ice-bath. triethylsilane (99.63 mg, 136.9 μL, 0.8568 mmol) was added followed slowly dropwise by TFA (2 mL,). The resulting mixture was stirred at 0° C. for ˜1 hour 50 minutes. The reaction mixture was concentrated under reduced pressure to give a light brown solid/gum. This material was partitioned with ether and brine. The ether layer was washed with 1M HCl (2×10 mL) and the combined aqueous layer was basified with saturated NaHCO3 and extracted with EtOAc (3×10 mL). The combined EtOAc was dried over Na2SO4, filtered and concentrated under reduced pressure to give a colourless gum (56.5 mg). This material was purified by column chromatography (4.5% MeOH/0.5% NH4OH in DCM, ˜75 mL silica, loaded in DCM) to give a white powder (15 mg, 20% Yield).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:10]=[CH:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1

Procedure:
2-Phenylethanol (3.1 g) was reacted with p-styrene sulfonyl chloride (5.3 g) and triethylamine (2.7 g) in 20 ml of dichloromethane for 3 hours to give the desired product as a light yellow viscous oil that was purified by passing through basic aluminum oxide.