Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20]([O:22][CH2:23]C)=[O:21])[CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc2cc(OCc3cccc(Cl)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 20 mg, 0.06 mmol) in MeOH (1 mL) and THF (1 mL) was added K2CO3. The reaction was stirred overnight at ambient temperature. The crude reaction mixture was concentrated onto silica and purification (FCC, SiO2, 0-40%, EtOAc/hexanes) afforded the title compound as a white solid (12 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 2H), 7.38-7.30 (m, 4H), 5.21 (s, 2H), 4.00 (s, 3H). [M+H]=328.2.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]([F:20])([F:19])[F:18])[C:13]=1[CH3:21]>>[CH3:21][C:13]1[C:14]([C:17]([F:20])([F:18])[F:19])=[N:15][O:16][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(C(F)(F)F)noc1N
Product: Cc1c(C(F)(F)F)noc1NS(=O)(=O)c1ccccc1
Yield: 72 %

Procedure:
This compound was prepared according to the method in Example 96 from benzenesulfonyl chloride and 5-amino-4-methyl-3-trifluoromethylisoxazole (see, U.S. Pat. No. 4,910,326 or corresponding EP A 0220947) in 72% yield as an off white solid after recrystallization from ethyl acetate/hexanes, m.p. 99.5°-100° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][N:18]=[N+]=[N-])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][NH2:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCC1CCCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCC1CCCN(C(=O)OCc2ccccc2)C1
Yield: 78.5 %

Procedure:
Dissolved 1-benzyloxycarbonyl-3-azidomethylpiperidine (1.27 g, 4.63 mmol, 1 eq) in THF (50 mL). Added water (10 mL). Added triphenylphosphine (1.5 g, 5.79 mmol, 1.25 eq) and let stir overnight. Removed solvent under reduced pressure and diluted the residue with 80 mL 1N HCl. Extracted the solution 3× with ethyl acetate to remove neutral organics. Basified the aqueous layer with 5N NaOH and extracted 3× with ethyl acetate. Combined the organic layers, dried over anhydrous Na2SO4, filtered and concentrated giving 903 mg of the desired amine.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10][CH:9]1[C:32](=[O:44])[NH:33][C:34]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH:35]1[CH:37]=[CH2:38])=O)(C)(C)C.C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:42]([O:41][C:39]([C:34]1([NH:33][C:32]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:15]=3)[CH2:12][NH:8]2)=[O:44])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:40])[CH3:43]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1)C(=O)OCC

Procedure:
Compound 11 was kept in TFA-DCM 1:2 (3 mL) at RT for 60 min. Toluene (3 mL) was added. The sample was co-evaporated to dryness. Purity by HPLC>95%. M+H+502.4.
Reaction SMILES: [OH:1][C:2]1([CH2:8][CH:9]([NH2:22])[CH2:10][N:11]([CH3:21])[C:12](=[O:20])[O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Si](Cl)(C)(C)C.Cl[C:29](OC1C=CC([N+]([O-])=O)=CC=1)=[O:30].Cl.[Cl:42][C:43]1[CH:44]=[C:45]([C@:49]([C@@H:57]2[CH2:62][CH2:61][CH2:60][NH:59][CH2:58]2)([OH:56])[CH2:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:46]=[CH:47][CH:48]=1>C(Cl)Cl.CCN(CC)CC>[Cl:42][C:43]1[CH:44]=[C:45]([C@:49]([C@@H:57]2[CH2:62][CH2:61][CH2:60][N:59]([C:29]([NH:22][CH:9]([CH2:8][C:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[CH2:10][N:11]([CH3:21])[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])=[O:30])[CH2:58]2)([OH:56])[CH2:50][CH2:51][CH2:52][CH2:53][O:54][CH3:55])[CH:46]=[CH:47][CH:48]=1
Reactant: CN(CC(N)CC1(O)CCCCC1)C(=O)OCC[Si](C)(C)C
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)NC(CN(C)C(=O)OCC[Si](C)(C)C)CC2(O)CCCCC2)C1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a solution of (2-(trimethylsilyl)ethyl 3-(1-hydroxycyclohexyl)-2-aminopropylmethylcarbamate (18.3 mg, 0.055 mmol) in CH2Cl2 (2 mL) were added Et3N (0.2 mL) and Me3SiCl (12 mg, 14 μL, 0.11 mmol). The resulting solution was stirred for 1 h and evaporated under vacuum. The residue was dissolved in CH2Cl2 (2 mL), then pyridine (0.05 mL) was added, followed by 4-nitrophenyl chloroformate (13.5 mg, 0.66 mmol). The mixture was stirred for 30 min and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol hydrochloride (19 mg, 0.055 mmol) was added. The mixture was stirred for 10 min and evaporated. The residue was purified by prep HPLC to give (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-(3-(1-hydroxycyclohexyl)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (20 mg, 54%). MS m/z 668 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=[O:14]>>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([N+:13]([O-:15])=[O:14])[CH2:17][CH3:18])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: CCC[N+](=O)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCC(=Cc1ccc(C(=O)OC)cc1)[N+](=O)[O-]

Procedure:
The title compound was prepared in an identical manner to that described in Description 27 using 4-carbomethoxybenzaldehyde and 1-nitropropane. τ (d6DMSO) 8.8 (3H, t, J=7 Hz), 8.08 (3H, s), 7.19 (2H, q, J=7 Hz), 6.12 (3H, s), 2.38 (2H, d, J=8 Hz), 1.97 (2H, d, J=8 Hz), 1.97 (1H, s).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:44][C:45]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:46]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:44][C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:46])[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccc1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-phenylethanone and isolated brown gum (0.8 mg, 5%). MS (m/e): 401.4 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:22])[C@@H:5]([O:20][CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH2:33].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][NH:33][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH3:21])[C:4]([OH:3])=[O:22])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OC
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccc(Cl)cc2Cl)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (PREPARATION 5, step 2) and 2-(2,4-dichloro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H25Cl2NO5 [M−H]−: 452, [M+H]: 454.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/C(O)=O)=[CH:4][C:3]=1[O:13][CH3:14].CC[N:17]([CH2:20]C)CC.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])C=CC=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH:8]=[CH:9][NH:17][C:20]2=[O:29])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CCN(CC)CC
Reactant: COc1cc(/C=C/C(=O)O)ccc1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COc1cc2cc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
A portion of the product from Step 1 (12.5 g, 48.6 mmol) was azeotroped with benzene and suspended in benzene (94 mL). Et3N (9.49 mL, 68.1 mmol) and diphenylphosphoryl azide (10.48 mL, 48.6 mmol) were added and the reaction mixture stirred at RT for 1 hour. The mixture was filtered through a pad of silica and eluted with ˜1 L of PhMe, the volatiles evaporated, the residue resuspended in diphenylmethane (94 mL) and the mixture heated to reflux for 3 hours (internal temperature 250° C.). The reaction mixture was allowed to cool to RT, stirred overnight, filtered and the solid washed with hexanes (100 mL) to give tan solid (7.4 g). LRMS ESI+ (M+H)+254.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:14][CH2:13][C:12]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[CH:11]2[OH:33])=[N:7][C:8]=1[Br:9].[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([C:12]2([C:15]([F:17])([F:18])[F:16])[CH2:13][CH2:14][N:10]([C:6]3[N:7]=[C:8]([Br:9])[C:3]([CH2:2][NH:1][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34])=[CH:4][CH:5]=3)[CH:11]2[OH:33])[CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=1
Reactant: NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Reactant: O=C(O)CC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC(F)(F)F)NCc1ccc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2O)nc1Br
Yield: 64.9 %

Procedure:
The mixture of 1-[5-(aminomethyl)-6-bromopyridin-2-yl]-3-[3,5-bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-2-ol (90 mg), 3,3,3-trifluoropropionic acid (31 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (62 mg), dichloromethane (10 ml) and a catalytic amount of 4-dimethylaminopyridine was stirred overnight at room temperature. Upon the completion of the reaction, the solvent was distilled off and the residue was purified by silica gel chromatography to obtain N-[(6-{3-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl}-2-bromopyridin-3-yl)methyl]-3,3,3-trifluoropropanamide (70 mg).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:10][C:11]1[C:12]([OH:20])=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=1)[CH:14]=O>C(O)(=O)C>[Br:10][C:11]1[C:12]([OH:20])=[C:13]([CH:16]=[C:17]([Br:19])[CH:18]=1)[CH:14]=[C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]1=[O:9]
Reactant: O=Cc1cc(Br)cc(Br)c1O
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cc(Br)cc(Br)c2O)C(=O)N1
Reaction time: 36 h
Yield: 84.6 %

Procedure:
0.01 mol (1.28 g) of barbituric acid (5a) were dissolved in 25 ml of glacial acetic acid while heating. Then 0.011 mol (3.08 g) of 3,5-dibromo-2-hydroxybenzaldehyde (6a) were added to the obtained solution while stirring and the resulting reaction mixture was left at room temperature during 36 hours. The produced crystal product was filtered, washed with cold acetic acid, then washed with ether and air-dried. Thereby 3.3 g of product 1a were obtained in the form of yellow needle crystals with melting temperature of 255-260° C. (with decomposition). Output amounted to 77% of the theoretical value.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl.C1(C)C=CC=CC=1>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][CH2:15][C:16]#[N:17])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: N#CCO[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of trans (4-cyanomethoxy-cyclohexyl)-carbamic acid tert-butyl ester (280 mg, 1.10 mmol) in DCM (22 mL) was treated with trifluoroacetic acid (22 mL) and stirred at ambient temperature for 30 minutes. The mixture was diluted with toluene and concentrated under vacuum. The residue was azeotroped with toluene to afford 450 mg (quantitative yield) of trans (4-amino-cyclohexyloxy)-acetonitrile trifluoroacetic acid salt as a colourless oil. LCMS (Method Q, ESI): RT=0.59 min, m+H=154.0; 1H NMR (400 MHz, DMSO) δ: 7.75 (br s, 2H), 4.43 (s, 2H), 3.35 (m, 1H), 2.95 (d, 1H), 1.99 (d, 2H), 1.90 (s, 2H), 1.25 (m, 4H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].[Cl:34][C:35]1C=CC(CN)=CC=1>>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH2:28][C:29]3[CH:33]=[CH:32][C:35]([Cl:34])=[CH:31][CH:30]=3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: Nc1nc(-n2cc(C(=O)NCC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NCc1ccc(Cl)cc1
Product: Nc1nc(-n2cc(C(=O)NCc3ccc(Cl)cc3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
Compound 22 was prepared in a manner similar to that of compound 21 using 4-chlorobenzylamine instead of cyclopentylamine, MS 501.19 (M+1).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][C:3](=[O:11])[O:2]1.[H-].C([Al+]CC(C)C)C(C)C.Cl.CCOCC>ClCCl>[CH2:1]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH2:4][CH:3]([OH:11])[O:2]1
Reactant: O=C1CC2CCCCC2CO1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Product: OC1CC2CCCCC2CO1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2.0 g (13 mmol) of (4a alpha, 8a alpha)(rac)-octahydro-3H-2-benzopyran-3-one in 65 mL of dry dichloromethane was added dropwise, over 30 min, 14 mL (14.3 mmol) of a 1.0 M solution of diisobutylaluminum hydride in dichloromethane. After further stirring at -78° C. for 45 min the mixture was warmed to 0° C. over 2 hours, stirred at 0° C. for 10 min, and then 1.0M aqueous HCl was added dropwise until a pH 0-1 was reached. After addition of 60 mL of ether, phase separation and extraction of the aqueous portion with 3×50 mL of ether, the combined organic solutions were washed with 5% KHCO3, dried (MgSO4) and concentrated under vacuum to 1.60 g (80%) of racemic (4a alpha, 8a alpha)-octahydro-1H-2-benzopyran-3-ol. TLC Rf 0.41 (SiO2, ether, molybdophosphoric acid-blue).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[Cl:8][CH2:9][C:10](Cl)=[O:11].[C:13](O)(=O)[CH2:14]C(CC(O)=O)(C(O)=O)O>O1CCCC1>[N:3]1([C:10](=[O:11])[CH2:9][Cl:8])[CH2:4][CH2:5][CH2:14][CH2:13][CH2:7][CH2:6]1
Reactant: O=C(Cl)CCl
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)N1CCCCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of hexamethyleneimine (2.9 ml) in tetrahydrofuran (25 ml) was added triethylamine (3.5 ml). Chloroacetyl chloride (2.0 ml) was added thereto on an ice bath followed by stirring for 1.5 hours while warming to room temperature. An aqueous solution of 10% citric acid was added thereto, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (3.5 g).
Reaction SMILES: C1([C:4]([C:13]([C:15]([CH:24]2[CH2:26]C2)=CC2C=CC=C(O)C=2)=O)=[CH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=2)CC1.O.[NH2:28][NH2:29]>O>[CH:15]1([C:13]2[CH2:4][CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=3)[NH:29][N:28]=2)[CH2:24][CH2:26]1
Reactant: NN
Reactant: O=C(C(=Cc1cccc(O)c1)C1CC1)C(=Cc1cccc(O)c1)C1CC1
Solvent: O
Product: Oc1cccc(C2CC(C3CC3)=NN2)c1
Yield: 67.6 %

Procedure:
To a 500 ml round bottom flask equipped with magnetic stirrer and reflux condenser was charged 13.2 g (0.0702 moles) of cyclopropyl 3-hydroxystyrylketone 150 mls of water and 3.5 g (0.0702 moles) of hydrazine monohydrate. The reaction was refluxed for a total of 2 hours, after which it was cooled and diluted with an additional 200 mls of water. The resulting solid was collected by vacuum filtration, washed with water and hexane, and dried in vacuuo at 40° C. overnight to afford 9.6 g of 3-cyclopropyl-5-(3-hydroxyphenyl)-2-pyrazoline as a tan solid at a 68% isolated yield.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[N:14][CH:15]=1.[F:17][C:18]([F:25])([F:24])[C:19](OCC)=O.[NH2:26][NH2:27]>CCO.CCOC(C)=O.C1COCC1>[Br:9][C:10]1[CH:11]=[C:12]2[C:19]([C:18]([F:25])([F:24])[F:17])=[N:27][NH:26][C:13]2=[N:14][CH:15]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NN
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1n[nH]c2ncc(Br)cc12
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
LDA, 2.0 M (15.63 mL, 31.3 mmol, Aldrich) was added to THF (35 ml) that was precooled to −78° C. under argon. The mixture was stirred for 5 min before 5-bromo-2-fluoropyridine (5.0 g, 28.4 mmol, Aldrich) was added dropwise. This mixture was stirred at −78° C. for 1.5 h and then ethyl 2,2,2-trifluoroacetate (5.65 g, 39.8 mmol, Aldrich) was added. The cooling bath was removed and the mixture was stirred for 1 h before 1N HCl and EtOAc were added. The layers were separated and the organic layer was dried with MgSO4, filtered, and concentrated to give a red oil. The oil was dissolved in EtOH (100 mL) and hydrazine (1.78 mL, 56.8 mmol, Aldrich) was added. This mixture was stirred at reflux for 2 h, cooled to RT, and diluted with EtOAc. The mixture was then washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo to give an oil that was precipitated with DCM. The solid was collected and the filtrate was concentrated and suspended in DCM again. The solid was collected and this time the filtrate was concentrated to give an oil which was purified by silica gel chromatography (0 to 50% EtOAc/hexane) affording 5-bromo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.4 g, 59%). MS (ESI, pos. ion) m/z: =266.1 (M+1). A mixture of 5-bromo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (158 mg, 0.59 mmol), bis(pinacolato)diboron (181 mg, 0.71 mmol), Pd(dppf)Cl2 (48.5 mg, 0.06 mmol, Strem) and potassium acetate (233 mg, 2.38 mmol, Aldrich) was capped, degassed and backfilled with argon (3×). Dioxane (5 mL) was added, and the reaction was heated at 100° C. After 22 h, the reaction mixture was cooled to 23° C., and filtered through celite. The crude reaction mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine was concentrated to dryness and taken forward to the next step.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.[F:12][C:13]([F:18])([F:17])[CH2:14][CH:15]=O.CC(O)=O.C([BH3-])#N.[Na+]>C1COCC1.CO>[F:12][C:13]([F:18])([F:17])[CH2:14][CH2:15][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=CCC(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(CCC(F)(F)F)CC1
Reaction time: 0.17 h
Yield: 68.2 %

Procedure:
To a solution of ethyl isonipecotate (3.00 g, 19.1 mmol) in THF (20 mL) and MeOH (20 mL) was added 3,3,3-trifluoropropionaldehyde (2.14 g, 19.1 mmol) and AcOH (1.09 mL, 19.1 mmol) followed by sodium cyanoborohydride (1.20 g, 19.1 mmol). The reaction was allowed to stir for 10 min., at which time the reaction was quenched with water (15 mL) then made basic with NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried and concentrated in vacuo to yield a white powder (3.3 g, 68%). Mass Spectrum: Calcd for C11H19NF3O2(M+H): 254. Found: 254.
Reaction SMILES: [CH3:1][C:2]1(CCCO)[C:7]2=[C:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[CH3:1][CH:2]1[C:7]2=[C:8]([CH3:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1.[S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)([O:3][CH2:2][CH2:7][CH3:8])(=[O:28])=[O:27]
Reactant: Cc1c2n(c3ccccc13)CCOC2(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCOS(=O)(=O)c1ccc(C)cc1
Product: Cc1c2n(c3ccccc13)CCOC2C

Procedure:
1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propanol (9.5 g.), described in Example 462, is dissolved in dry pyridine (20 ml.). p-Toluenesulfonyl chloride (7.4 g.) is added portionwise to the vigorously stirred and cooled solution. The mixture is stirred further at 0°C. for 1 hr., ice and water is then added and the aqueous mixture is extracted with ether. The combined ether extracts are washed with 10% ice-cold hydrochloric acid, water, 5% sodium bicarbonate water and dried (Na2SO4). Concentration of the extracts affords 1,10-dimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propyl tosylate, δCHCl3max 1600, 1370, 1190 and 1170 cm-1.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][N:6]=1.[C:9]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[C:7]([C:4]1[S:3][C:2]([O:23][C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:22][CH:21]=2)=[N:6][CH:5]=1)#[N:8]
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ncc(C#N)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
2-chloro-thiazole-5-carbonitrile (900 mg 6.2 mmol; prepared according to procedure described in WO 01/17995, p. 103) and N-Boc-4-hydroxy-aniline (1.3 g, 6.2 mmol) were combined in N,N-dimethyl formamide (5 mL). To this solution, K2CO3 (2.6 g, 18.8 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate (2×). The combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by flash column chromatography (ethyl acetate:hexanes: 5%-50% ethyl acetate gradient) to give the title compound (2.0 g, 6.2 mmol, 100%) as a white solid. MS (ESI APCI) m/z 316.0 (M−H+); 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H) 8.24 (s, 1H) 7.58 (d, J=9.0 Hz, 2H) 7.36 (d, J=9.0 Hz, 2H) 1.48 (s, 9H).