Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]#[C:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1cccc(CC#CC2CCNCC2)n1
Product: Cc1cccc(C#CCC2CCN(c3ncccc3[N+](=O)[O-])CC2)n1
Yield: 54.1 %

Procedure:
A well homogenised mixture of Compound 31a (24 mg, 0.11 mmol) and 2-chloro-3-nitropyridine (19.5 mg, 0.12 mmol) was stirred at 120° C. for 40 min. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 3:7) affording the title product (20 mg).
Reaction SMILES: Cl.CC1(C)[O:7][C@@H:6]2[CH2:8][CH2:9][CH2:10][C@@H:11]([NH:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[CH:34]=[CH:33][C:32]6[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=6[CH:26]=5)[N:20]=4)[CH2:15][CH2:14]3)[C@@H:5]2[O:4]1>CO>[CH3:35][C:31]1([CH3:36])[CH2:30][CH2:29][C:28]([CH3:37])([CH3:38])[C:27]2[CH:26]=[C:25]([C:21]3[N:20]=[C:19]([N:16]4[CH2:15][CH2:14][CH:13]([NH:12][C@@H:11]5[CH2:10][CH2:9][CH2:8][C@@H:6]([OH:7])[C@H:5]5[OH:4])[CH2:18][CH2:17]4)[CH:24]=[CH:23][CH:22]=3)[CH:34]=[CH:33][C:32]1=2
Reactant: CC1(C)O[C@H]2[C@H](NC3CCN(c4cccc(-c5ccc6c(c5)C(C)(C)CCC6(C)C)n4)CC3)CCC[C@H]2O1
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(N[C@@H]5CCC[C@@H](O)[C@H]5O)CC4)n3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 ml of 1.25 N HCl in methanol are added to 91 mg of ((3aS,4R,7aR)-2,2-dimethylhexahydrobenzo-1,3-dioxol-4-yl)-[6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,4,5,6-tetrahydro-2H-1,2′-bipyridinyl-4-yl]amine, and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated and dried under high vacuum. The product is in the form of the hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[C:7]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:6]1.FC(F)(F)C([O-])=O.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[CH3:51][C:52]1([C:56](O)=[O:57])[CH2:55][O:54][CH2:53]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:56]([C:52]3([CH3:51])[CH2:55][O:54][CH2:53]3)=[O:57])[CH2:9][C:8]=2[C:7]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[N:6]1
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Reactant: CC1(C(=O)O)COC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CCc3c(c(-c4cccc(C#N)c4)nn3Cc3ccc(F)cc3F)C2)COC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 10° C. cold solution of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile, trifluoroacetate (7c) (0.055 g, 0.118 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (18 μl, 0.13 mmol), 1-hydroxybenzotriazole (17 mg, 0.124 mmol), 3-methyl-3-oxetane carboxylic acid (13.8 mg) and finally 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24 mg, 0.124 mmol). The mixture was allowed to warm to 25° C. and stirred for 16 h and purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 38 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-oxetane-3-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8a).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[NH:11][C:10]=1[C:24]([OH:26])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:27]([O:34][CH2:35][CH2:36][NH:37][CH:38]([CH3:40])[CH3:39])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Si:27]([O:34][CH2:35][CH2:36][N:37]([CH:38]([CH3:40])[CH3:39])[C:24]([C:10]1[NH:11][C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])=[N:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:26])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: O=C(O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Yield: 51 %

Procedure:
5-(Benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid (68) (1 g, 2.41 mmol, Eq: 1.00) was dissolved in pyridine (20 ml) and N-(2-(tert-butyldimethylsilyloxy)ethyl)propan-2-amine (8b) (576 mg, 2.65 mmol, Eq: 1.1) was added. Precipitate formed and gave a thick slurry. Additional 5 ml of pyridine were added to ease stirring. The suspension was cooled in an ice/NaCl bath. POCl3 (1.11 g, 673 μl, 7.22 mmol, Eq: 3) was added dropwise, keeping the inside temperature below 0° C. After the addition was complete the mixture was stirred for 45 minutes at 0° C. The reaction was quenched with ice and the organic solvent was mostly removed. The remaining aqueous layer was extracted three times with ethyl acetate. The organic layers were washed with brine, combined, dried over Na2SO4, filtered and concentrated. The remaining oil was taken up in a little dichloromethane, was filtered through Celite and then purified by SiO2 flash chromatography (80 g SiO2, hexanes/ethyl acetate 0-50% ethyl acetate) to afford 5-benzyloxy-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (69) (0.758 g, 1.23 mmol, 51.2% yield) as a light brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[CH:13]=[C:12]2[CH3:30])[CH:5]=1.CSC.B.CO>C1COCC1>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:29])([C:25]([F:27])([F:28])[F:26])[C:21]([F:23])([F:22])[F:24])=[CH:17][CH:18]=2)[CH:13]=[C:12]1[CH3:30])[CH3:32]
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)N(C)C)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(CN(C)C)c1
Temperature: 70 °C
Reaction time: 10 h
Yield: 73.5 %

Procedure:
A solution of 7 mg (0.0153 mmol) of N,N-dimethyl-3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzamide (example 34) in 0.2 mL of THF was treated with 0.006 mL (0.031 mmol) of borane dimethylsulfide. The mixture was stirred at 70° C. for 10 hrs, treated with MeOH, and concentrated. Column chromatography on silica gel with n-heptane/EtOAc 4:1 to 1:1 yielded 5 mg (72%) of 2-[1-(3-dimethylaminomethyl-benzyl)-2-methyl-1H-indol-5-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow oil, MS: 445 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15]Cl>>[OH:17][CH:14]([CH2:13][OH:18])[CH2:15][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: OCC(O)CCl
Reactant: O=C1CCc2ccc(O)cc2N1
Product: O=C1CCc2ccc(OCC(O)CO)cc2N1

Procedure:
In the same manner as described in Example 7, 7-hydroxy-3,4-dihydrocarbostyril was reacted with glycerol α-monochlorohydrin to give 7-(2,3-dihydroxy)propoxy-3,4-dihyrocarbostyril as white needle-like srystals having a melting point of 143° - 144° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15]([CH:17]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[C:11](=O)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH:10]([NH:14][C:15]([CH:17]([O:22][C:23]([N:25]1[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1)=[O:24])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(OC(=O)N1CCOCC1)C(=O)NC(COCc1ccccc1)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)CC(OC(=O)N1CCOCC1)C(=O)NC(C#N)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
Morpholine-4-carboxylic acid 1-(2-benzyloxy-1-carbamoyl-ethylcarbamoyl)-3-methyl-butyl ester (0.100 g, 0.23 mmol) was dissolved in 3 mL of DMF and cooled to 0° C. with an ice-water bath. To this solution was added cyanuric chloride (0.044 g, 0.23 mmol) and the reaction mixture was stirred for 1 h. The reaction was quenched with cold water (2 mL), extracted with EtOAc (3×100 mL), and the organic layers were combined and washed with 100 mL brine. The organic layer was dried over MgSO4, filtered and concentrated to give the crude residue. The residue was purified by chromatography (SiO2, 50% hexane in EtOAc) to give the title compound as a clear oil (0.055 g, 60%); 1H NMR (CDCl3) 7.35 (5H, m), 6.76 (1H, d), 5.1 (2H, m), 4.65 (2H, m), 3.82-3.35 (10H, m), 1.7 (3H, m), 0.95 (6H, m). MS: m/z=404 M+1.
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.[OH2:22]>>[OH:22][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Reactant: O
Agent: Br
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1

Procedure:
treating the reaction mixture containing the compound (VI) directly with water and reacting by stirring at 50°-100° C., preferably at 60°-80° C., to give 3(R,S)-hydroxy-1-methyl4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII), and
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH:31]([CH3:33])[CH3:32]>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:23]1[CH:24]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=1[CH:31]([CH3:33])[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(S(C)(=O)=O)cc1I
Product: CC(C)c1ccc(S(C)(=O)=O)cc1C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Yield: 74 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46) and 2-iodo-1-isopropyl-4-(methylsulfonyl)benzene (Intermediate 91), the title compound was obtained as a brown solid in 74% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28].N1C=CC=CC=1>C(OCC)C>[C:27](=[O:28])([O:29][CH2:30][CH3:31])[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione and ethyl chloroformate with pyridine in diethyl ether there is obtained 2-[2-chloro-5-(3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorophenoxy]-ethyl ethyl carbonate, 1H-NMR (CDCl3, 400 MHz): 7.32 ppm (d,1H), 6.81 ppm (d,1H), 6.36 ppm (s,1H), 4.47°-4.54 ppm (m,2H), 4.16°-4.27 ppm (m,4H), 3.56 ppm (d,3H), 1.32 ppm (t,3H);
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>Cl.O>[CH:1](=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: Nc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccccc1
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a mixture of salicylaldehyde (40 mL, 45.84 g, 375.37 mmol)) and aniline (22 mL, 31.72 g, 374.66 mmol), was added ethanol (90 mL), 8 drops of concentrated hydrochloric acid and water (10 mL). This reaction mixture was refluxed for one hour, allowed to cool to room temperature and left in the refrigerator over the weekend. A large quantity of orange solid was formed after 2 hours in the refrigerator. It was filtered off and washed with ethanol. Recrystallisation from ethanol afforded 31.53 g of product.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH2:4][OH:5].[Na].Cl[C:14]1[NH:19][C:18](=[O:20])[C:17]([F:21])=[CH:16][N:15]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:3][CH2:4][O:5][C:14]1[NH:19][C:18](=[O:20])[C:17]([F:21])=[CH:16][N:15]=1
Reactant: CC(C)=CCCC(C)=CCO
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: [Na]
Solvent: Cc1ccccc1
Product: CC(C)=CCCC(C)=CCOc1ncc(F)c(=O)[nH]1
Yield: 61 %

Procedure:
23.1 g of 3,7-dimethyl-2,6-octadien-1-ol and 3.4 g of metal sodium are added to 200 ml of absolute toluene, and the mixture is stirred at 40° to 50° C until the metal sodium has been completely dissolved. Subsequently 7.4 g of 2-chloro-5-fluoropyrimidin-4-one is added to the solution, and the mixture is refluxed for 8 hours. The solvent is distilled off from the resulting reaction mixture, 30 ml of water is added to the residue and the pH of the mixture is adjusted to 4-5 with dilute hydrochloric acid. The resulting mixture is extracted with 200 ml of chloroform and the extract is concentrated. Purification of the residue by silica gel column chromatography gives 8.3 g of slightly yellow oily 2-(3,7-dimethyl-2,6-octadien-1-oxy)-5-fluoropyrimidin-4-one in a yield of 61.0 %.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([O:18]C)=[O:17])=[N:14][CH:15]=1.[OH-].[Na+].Cl>CO.[Cl-].[Na+].O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[N:14][CH:15]=1
Reactant: COC(=O)c1cnc(CCOC2CCCCO2)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(CCOC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.4 %

Procedure:
To a solution of methyl 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazine-2-carboxylate (1.36 g) in methanol (20 mL) was added 1 M aqueous sodium hydroxide solution (15 mL) under ice-cooling. It was stirred at room temperature for 2 hours. To the reaction mixture was added 1 M hydrochloric acid under ice-cooling to adjust the pH to 3. A saturated brine was added, followed by extraction with a solvent (chloroform:methanol=4:1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazine-2-carboxylic acid (1.50 g) as a brown oily substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([C:14]3[C:15]([CH3:20])=[N:16][NH:17][C:18]=3[NH2:19])=[N:11][C:10]=2[CH:21]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:19][C:18]1[NH:17][N:16]=[C:15]([CH3:20])[C:14]=1[C:12]1[S:13][C:9]2[CH:8]=[CH:7][C:6]([CH2:4][OH:3])=[CH:21][C:10]=2[N:11]=1
Reactant: CCOC(=O)c1ccc2sc(-c3c(C)n[nH]c3N)nc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1n[nH]c(N)c1-c1nc2cc(CO)ccc2s1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a solution of 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-5-carboxylic acid ethyl ester (30 mg) in THF (1 mL) was added lithium aluminum hydride (4 mg). The reaction mixture was stirred at room temperature for 5 hrs at which point sodium sulfate nonahydrate was added. The resulting mixture was stirred for an additional 30 min. The solids were removed by filtration. The solvent was then evaporated and the residue was purified by flash column chromatography eluting with CHCl3:MeOH=9:1 to yield 21 mg (81%) of the title compound as a cream coloured solid. MS (m/z, ES+): 261.1 (M+1, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C@H:6]([C:26](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:27])[C@@H:7]([C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[OH:8].[Li+].[OH-].OO.C(OCC)(=[O:51])C>C1COCC1.O>[F:44][C:42]1[CH:41]=[C:4]([CH:3]=[C:2]([F:1])[CH:43]=1)[CH2:5][C@@H:6]([C@@H:7]([C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[OH:8])[C:26]([OH:51])=[O:27]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CCOC(C)=O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-tert-butyl 3-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (4), 13.0 g, 21.5 mmol) in THF (500 mL) was added a solution of LiOH (1.03 g, 43 mmol) in H2O (100 mL), then 30% H2O2 (24.4 g) was added at 0° C. This reaction mixture was warmed up to rt over 1 h and stirred at rt for 4 h. Ethyl acetate (1000 mL) was added and washed with 1N HCl, and H2O, dried (Na2SO4), and concentrated in vacuo to give the crude product which was ready for next step without purification. MS (ESI) (M−H)− 446.07.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17]C)=[O:16])[CH2:12][CH2:11][N:10]2[C:19]([O:21][CH3:22])=[O:20])=[CH:5][CH:4]=1.[Br-].[Li+].CCN(CC)CC.CC(OC)(C)C>C(#N)C.O>[CH3:22][O:21][C:19]([N:10]1[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][CH:9]1[C:6]1[CH:7]=[N:8][C:3]([C:2]([F:23])([F:1])[F:24])=[CH:4][CH:5]=1)=[O:20]
Reactant: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)nc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(F)(F)F)nc1
Yield: 89.8 %

Procedure:
Crude dimethyl 2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-1,4-dicarboxylate (2.9 g, 8.38 mmol) was dissolved in acetonitrile (35 mL) and water (0.700 mL), then lithium bromide (2.91 g, 33.50 mmol) was added. Et3N (2.334 mL, 16.75 mmol) was added and the resulting yellow suspension was heated under reflux for 1 h. Water (100 mL) and MTBE (150 mL) were added. The phases were separated and the organic layer was extracted with water (2 times). The pooled water layers were acidified to pH 1 with 3.8 M HCl and extracted into MTBE (2 times). The combined organic layer was dried over Na2SO4, filtered and evaporated yielding crude 1-(methoxycarbonyl)-2-(6-(trifluoromethyl)pyridin-3-yl)piperidine-4-carboxylic acid (2.5 g, 90%) as a slightly yellow solid. MS m/z 333 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[CH3:15][O:16][C:17]([C:19]1[CH:29]=[C:28]([OH:30])[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=2[CH:20]=1)=[O:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]([O:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:30][C:28]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:29]=2)=[CH:7][N:6]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)nc2)c2c(c1)OC(C)(C)C2
Temperature: 100 °C
Yield: 2.9 %

Procedure:
A mixture of t-butyl 5-bromopicolinate (581 mg, 2.25 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K3PO4 (956 mg, 4.50 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (96 mg, 0.225 mmol), and Pd(OAc)2 (51 mg, 0.225 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 3 h, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 15-30% EtOAc in hexanes to give 26 mg of 5-(6-Methoxycarbonyl-2,2-dimethyl-2,3-dihydro-benzofuran-4-yloxy)-pyridine-2-carboxylic acid tert-butyl ester and 400 mg mixture of the title compound with ˜40% of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=2.53 Hz, 1 H) 8.05 (d, J=8.84 Hz, 1 H) 7.23-7.36 (m, 2 H) 7.19 (d, J=1.26 Hz, 1 H) 3.87 (s, 3 H) 2.89 (s, 2 H) 1.64 (s, 9 H) 1.48 (s, 6 H); LCMS for C22H25NO6 m/z 344.00 (M−tBu+H+).
Reaction SMILES: [O:1]=[C:2]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:27]([CH2:28][CH2:29][C@:7]12[CH3:8])[C@:20]1([CH2:21][O:22]C(=O)CC)[C:15](=[CH:16][C:17](=[O:30])[CH2:18][CH2:19]1)[CH2:14][CH2:13]3)[CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[OH:22][CH2:21][C@@:20]12[C@@H:27]3[C@H:12]([C@H:9]4[C@@:7]([CH2:29][CH2:28]3)([CH3:8])[C@@H:6]([O:5][C:2](=[O:1])[CH2:3][CH3:4])[CH2:11][CH2:10]4)[CH2:13][CH2:14][C:15]1=[CH:16][C:17](=[O:30])[CH2:18][CH2:19]2
Reactant: CCC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CC)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@]12C

Procedure:
A solution of 11 g of 17β,19-bis(1-oxopropoxy)androst-4-en-3-one in 2 liters of methanol is treated with 2.5 g of sodium carbonate in 250 ml of water and refluxed for one hour after which the reaction mixture is poured into 10 liters of water, and the solid collected by filtration. The solid is dissolved in methylene chloride, dried over magnesium sulfate, filtered and the solvent removed. The residue is crystallized from acetone-hexane yielding 6 g of 19-hydroxy-17β(1-oxopropoxy)androst-4-en-3-one. M.P. 160°-162° C.
Reaction SMILES: [C:1]1([C:6]([NH:8][NH:9][C:10]([NH:12][CH3:13])=[S:11])=O)[S:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].Cl>>[CH3:13][N:12]1[C:6]([C:1]2[S:5][CH:4]=[CH:3][CH:2]=2)=[N:8][NH:9][C:10]1=[S:11]
Reactant: CNC(=S)NNC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2cccs2)n[nH]c1=S

Procedure:
1-(2-Thenoyl)-4-methylthiosemicarbazide (7.1 g, 3.3×10-2 mole) and 1 molar aqueous NaHCO3 (330 ml, 3.30×10-1 mole) were stirred and heated to reflux. After refluxing about 14 hours the reaction was filtered while hot and the filtrate was then cooled in an ice bath. Acidification by the dropwise addition of concentrated HCl (28 ml, 3.4×10-1 mole) gave a colorless precipitate which was collected by filtration, washed with a little cold H2O, and dried by suction. Crystallization from isopropanol gave colorless spears: 5.0 g (77%), mp 155°-157° C.