Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C(=O)[N:14]2C(C(C)=C([Cl:18])[C:12](F)=[CH:13]2)=C(C2CC2)C=1)=O)C.C(=O)(O)[O-].[Na+].Cl.CN(C)[C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]2[C:37]([F:54])=[CH:38][N:39]3[C:44]([C:45]=2[CH3:46])=[C:43]([CH:47]2[CH2:49][CH2:48]2)[CH:42]=[C:41]([C:50]([OH:52])=[O:51])[C:40]3=[O:53])[CH2:32]1.C(OC(NC(N1CCCC1)C)=O)(C)(C)C>C(#N)C>[ClH:18].[NH2:14][C@@H:13]([C@@H:31]1[CH2:35][CH2:34][N:33]([C:36]2[C:37]([F:54])=[CH:38][N:39]3[C:44]([C:45]=2[CH3:46])=[C:43]([CH:47]2[CH2:49][CH2:48]2)[CH:42]=[C:41]([C:50]([OH:52])=[O:51])[C:40]3=[O:53])[CH2:32]1)[CH3:12]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: Cc1c(N2CC[C@@H](N(C)C)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12
Agent: CC(NC(=O)OC(C)(C)C)N1CCCC1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: Cc1c(N2CC[C@@H]([C@@H](C)N)C2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 0.35 g sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, and 0.73 g of sodium bicarbonate were dissolved in 24 mL of anhydrous acetonitrile, reacted with (3R, 1R)-3-(1-(t-butoxycarbonylamino)ethyl -pyrrolidine (0.51 g, prepared as described by Schroeder et al., J. Heterocyclic Chem., 29:1481-1498 (1992)), and carried forward as described in Example 253k-l to give the title product. mp 220°-222° C. MS 374 (M+H)+ ; 1H NMR (D6 -DMSO) ∂: 0.61 (m, 2H), 0.94 (m, 1H), 1.07 (m, 1H), 1.28 (d, 3H, J=6 Hz), 1.82 (m, 1H) 2.27 (m, 2H), 2.46 (m, 1H), 2.62 (s, 3H), 3.57 (s, 1H), 3.92 (m, 1H), 7.90 (s, 1H), 8.17 (br s, 3H), 9.07 (d, 1H, J=11 Hz), 13.84 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1.I.O.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)/C=C/C(=O)c1ccc(-c2ccccc2F)cc1
Agent: I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCCc1ccc(-c2ccccc2F)cc1

Procedure:
1.10 gm (0.004 mol) of 4-(2'-fluoro-4-biphenylyl)-4-oxo-crotonic acid were refluxed while stirring, in 10 ml of glacial acetic acid and 20 ml hydroiodic acid (d=2.00) for 12 hours. Subsequently, the solution was poured into 200 ml of water, the aqueous mixture was decolorized with sodium bisulfite, and extracted twice with 100 ml of ether each. The ether solution was washed with water and evaporated; the solid residue was refluxed with 150 ml of cyclohexane, the undissolved starting material was vacuum-filtered off, and the cyclohexane solution was evaporated to dryness. The residue was dissolved in 20 ml of ethyl acetate, and by addition of cyclohexylamine the cyclohexylamine salt of 4-(2'-fluoro-4-biphenylyl)-butyric acid was precipitated; m.p. 132°-134° C., after recrystallization from ethyl acetate/ethanol. Yield: 0.60 gm.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CN=CC=1.[CH2:17]([O:19][N:20]=[C:21]([C:25]1[C:26](=[O:39])[CH2:27][CH:28]([C:32]2[S:33][C:34]([CH3:38])=[C:35]([CH3:37])[N:36]=2)[CH2:29][C:30]=1[OH:31])[CH2:22][CH2:23][CH3:24])[CH3:18]>ClCCl>[CH2:17]([O:19][N:20]=[C:21]([C:25]1[C:26](=[O:39])[CH2:27][CH:28]([C:32]2[S:33][C:34]([CH3:38])=[C:35]([CH3:37])[N:36]=2)[CH2:29][C:30]=1[O:31][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH2:23][CH3:24])[CH3:18]
Reactant: CCCC(=NOCC)C1=C(O)CC(c2nc(C)c(C)s2)CC1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccncc1
Solvent: ClCCl
Product: CCCC(=NOCC)C1=C(OC(=O)c2ccccc2)CC(c2nc(C)c(C)s2)CC1=O
Yield: 79.2 %

Procedure:
Benzoyl chloride (0.12 g) and 4-methylpyridine (0.08 g) were added dropwise with stirring to a solution of 2-[1-(ethoxyimino)butyl]-5-(4,5-dimethyl-2-thiazolyl)-3-hydroxycyclohex-2-en-1-one (2) (0.27 g) in dichloromethane (40 ml) at ambient temperature. After 1 hour the solution was washed with cold dilute aqueous sodium hydroxide, followed by cold dilute hydrochloric acid and then dried over magnesium sulphate and evaporated to give 2-[1-(ethoxyimino)butyl]-3-benzoyloxy-5-(4,5-dimethyl-2-thiazolyl)cyclohex-2-en-1-one (0.28 g, 80%) as an orange oil. The product was characterized by proton nuclear magnetic resonance spectroscopy and appropriate physical data are recorded in Example 5 Table 6.
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])[C@@H:12]2[C@@H:15](OS(C)(=O)=O)[CH3:16])[C:9]=1[C:23]([O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:3])[CH3:2].N12CCCCC1C=NCCC2>ClCCl>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:22])/[C:12]/2=[CH:15]\[CH3:16])[C:9]=1[C:23]([O:25][Si:26]([C:39]([CH3:40])([CH3:42])[CH3:41])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N2C(=O)[C@H]([C@H](C)OS(C)(=O)=O)[C@H]2C1
Agent: C1=NCCCN2CCCCC12
Solvent: ClCCl
Product: C/C=C1\C(=O)N2C(C(=O)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)=C(S/C=C/NC(C)=O)C[C@H]12
Yield: 40.1 %

Procedure:
tert-Butyldiphenylsilyl (5R,6S)-3-[(E)-2-acetamidoethenylthio]-6-[(1S)-1-methylsulphonyloxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (20 mg) in dichloromethane (1 ml) was treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.05 ml of a 100 mg/ml solution in CH2Cl2) at room temperature for 20 min. The dichloromethane solution was diluted, washed with water, dried (MgSO4) and evaporated in vacuo to give tert-Butyldiphenylsilyl (5R)-3-[(E)-2-acetamidoethenylthio]-6-[(Z)-ethylidene]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (e67) (6.8 mg). νmax 1770, 1700, 1675, 1640, 1620 cm-1. δ(CDCl3 +D2O) 1.11[9H,s,C(CH3)3 ], 1.85 (3H,s,CH3CO), 2.05 (3H,d,J approx. 7 Hz, CH3CH), 3.7-3.3 (2H,m, 4--CH2), 4.4-4.7 (1 H,m, 5--CH), 5.65 (1H,d,J 14 Hz, SCH=CH), 5.83 (1H, broadened q, J ca 7 Hz, CH3CH), 7.00 (1H,d,J 14 Hz CHNH), 7.2-7.8 (10H,m,Ar--H).
Reaction SMILES: N#N.[C:3]1([CH2:9][N:10]2[CH2:22][CH2:21][C:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1>[C:3]1([CH2:9][N:10]2[CH2:22][CH2:21][C@H:13]3[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C@@H:12]3[CH2:11]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(CN2CCc3[nH]c4ccccc4c3C2)cc1
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Product: c1ccc(CN2CC[C@H]3Nc4ccccc4[C@@H]3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
Borane-THF complex (1:1) (400 ml) was transferred into a 4 necked flask with a syringe (under N2 flow). This solution was cooled to 0° C. A solution of 2,3,4,5-tetra-hydro-2-(phenylmethyl)-1H-pyrido[4,3-b]indole (52.5 g), prepared as described in J. Med. Chem. 9:436-438 (1966), in THF (400 ml) was added over a 1 hour period at 0-5° C. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was stirred and refluxed for 4 hours, then cooled to room temperature. 6N HCl (300 ml) was added. The organic solvent was removed by evaporation. Dioxane (400 ml) was added to the residue and the mixture was stirred and refluxed for 1 hour. The solvent was evaporated. Water (300 ml) was added to the residue and this mixture was alkalized with a diluted NaOH solution. This mixture was extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue (20 g) was crystallized from DIPE (100 ml). The crystals were filtered off and dried, yielding 7.5 g (14%) of (±)-trans-1,3,4,4a,5,9b-hexahydro-2-(phenylmethyl)-2H-pyrido[4,3-b]indole (intermediate 13).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[C:22]([O:27][C:2]1[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=1)[CH:21]=2
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1cc2ccc(O)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)cc2[nH]1
Temperature: 120 °C
Reaction time: 24 h
Yield: 36.6 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (360 mg, 1.1 mmol), 2-methyl-1H-indole-6-ol (320 mg, 2.2 mmol), potassium carbonate (450 mg, 3.3 mmol) and N,N-dimethylformamide (4 mL) was stirred at 120° C. for 24 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→90/10) to give the title compound (140 mg, 36%) as a brown solid.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:7]2=[CH:6]1)C(C)C.IC>>[CH3:15][C:12]1([CH3:16])[C:8]2[C:7](=[CH:6][N:5]([CH3:1])[C:10](=[O:11])[CH:9]=2)[NH:14][CH2:13]1
Reactant: CC(C)Cn1cc2c(cc1=O)C(C)(C)CN2
Solvent: CI
Product: Cn1cc2c(cc1=O)C(C)(C)CN2

Procedure:
Prepared in an analogous method to 6-isobutyl-3,3-dimethyl-1,2,3,6-tetrahydro-pyrrolo[2,3-c]pyridin-5-one using iodomethane instead of 3-bromo-2-methylpropene and omitting the hydrogenation step (see Preparations 128 and 130).
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]3[C:41]=2[CH:42]=O)=[CH:28][CH:27]=1.[CH3:44][C:45]1[O:46][CH:47]=[N:48][N:49]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]3[C:41]=2[CH2:42][C:47]2[O:46][C:45]([CH3:44])=[N:49][N:48]=2)=[CH:30][CH:31]=1
Reactant: Cc1nnco1
Reactant: Cc1ccc2nc(-c3ccc(Cl)cc3)c(C=O)n2c1
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1ccc2nc(-c3ccc(Cl)cc3)c(Cc3nnc(C)o3)n2c1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine-3-carbaldehyde and 2-methyl-1,3,4-oxadiazole. M/e+ 339 for C18H16ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.10 (dd, J=9.1, 1.4 Hz, 1H), 4.54 (s, 2H), 2.49 (s, 3H), 2.35 (s, 3H) ppm.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17].[CH:20]1([C:23]2[C:32]([CH:33]=[O:34])=[C:31]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:22][CH2:21]1>C1COCC1>[CH3:13][O:14][N:15]([CH3:19])[C:16](=[O:18])[CH2:17][CH:33]([C:32]1[C:23]([CH:20]2[CH2:21][CH2:22]2)=[N:24][C:25]2[C:30]([C:31]=1[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:34]
Reactant: CON(C)C(C)=O
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CON(C)C(=O)CC(O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
Butyllithium (1.64M hexane solution, 7.54 ml, 12.4 mmol) was added to a THF (40 ml) solution of diisopropylamine (1.25 g, 12.4 mmol) at -78° C. and the mixture was stirred for 15 minutes. Thereto was added a THF (20 ml) solution of N-methoxy-N-methylacetamide (1.27 g, 12.3 mmol) at -78° C., and the resulting mixture was stirred at -78° C. for 15 minutes. To this mixture was added a THF (40 ml) solution of 2-cyclopropyl-4-(4-fluorophenyl)-3-formylquinoline (3.00 g, 10.3 mmol). The reaction mixture was stirred at -78° C. to room temperature over a period of 3 hours before quenching with water and extraction with diethyl ether. The ethereal organic layer was washed with saturated sodium chloride aq solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (hexane:ethyl acetate=2:1) to give N-methoxy-N-methyl-3-{2-cyclopropyl- 4-(4-fluorophenyl)quinoline-3-yl}-3-hydroxypropanamide (3.70 g, 91% yield). Rf =0.30 (hexane:ethyl acetate=2:1) IR (CHCl3): 3450, 3000, 1640, 1515, 1490, 1420, 1230, 1070, 780 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>S(=O)(=O)(O)O>[Br:18][C:7]1[C:6]([F:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: N#Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of compound 2,6-difluorobenzonitrile (5 g, 36 mmol) in concentrated sulfuric acid (25 mL) was added with NBS (7 g, 39.6 mmol) at 0° C. and stirred at ambient temperature for 2 days. Ice was added to the reaction solution. The mixture was extracted with EtOAc. The organic layer was washed with water, saturated NaHCO3 solution, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified with fast column chromatograph to give compound 3-bromo-2,6-difluorobenzonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 7.78˜7.83 (m, 1H), 6.98˜7.03 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12].[H-].[Na+].F[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]2[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)c1cc2c(Cl)cc(O)cc2n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)cc(Oc3ccc([N+](=O)[O-])cc3)cc2n1C

Procedure:
The reaction was carried out in a manner similar to Example 186 a) except for using 0.41 g (1.62 mmol) of ethyl 4-chloro-6-hydroxy-1-methyl-2-indolecarboxylate, 0.09 g (2.23 mmol) of 60% sodium hydride, 0.34 g (2.40 mmol) of 1-fluoro-4-nitrobenzene and 5 ml of dimethylformamide. Ethyl 4-chloro-1-methyl-6-(4-nitrophenoxy)-2-indolecarboxylate was thus obtained in an amount of 0.51 g (92.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C@@:24]12(O)[N:31](C)[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=C2.[Na].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][C@@:9]12[N:31]([CH3:24])[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=[CH:10]2)=[O:7]
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: CCOC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1)CC2

Procedure:
4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. The residue remaining is mixed with diethylether/petroleum ether (1:9), suction filtered and washed. Yield: 2.50 g (46% of theory); TLC: Rf value: 0.29 (eluent: sec-butanol/formic acid/water (75:15:10)); melting point: 147° C.-148° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.Cl.Cl[CH2:34][CH2:35][CH:36]1[CH2:40][CH2:39][CH2:38][N:37]1[CH3:41].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CC(C)=O>[CH3:41][N:37]1[CH2:38][CH2:39][CH2:40][CH:36]1[CH2:35][CH2:34][O:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4OCCC4CCCN4C)ncn3)cccc2s1
Temperature: 150 °C

Procedure:
A mixture of N-(4-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)benzo[d]thiazol-2-yl)-acetamide (89 mg, 0.2 mmol, prepared as described in WO04014871), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (56 mg, 0.3 mmol, Aldrich), sodium carbonate (62 mg, 0.6 mmol, Aldrich), sodium iodide (45 mg, 0.3 mmol) and acetone (1 mL) was heated in a microwave synthesizer at 150° C. for 40 min. The reaction mixture diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (10% MeOH/CH2Cl2) to give the title compound as an amorphous solid. MS (ESI, pos. ion.) m/z: 558 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.C(Cl)(=O)OCC.[N+:27](=[CH2:29])=[N-:28]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH3:13])[C:10](=[O:12])[CH:29]=[N+:27]=[N-:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a −15° C. solution of 2-((tert-butoxycarbonyl)amino)propanoic acid (2.5 g, 13.21 mmol) in THF (66 mL) was added Et3N (1.337 g, 13.21 mmol) and ethyl carbonochloridate (1.434 g, 13.21 mmol). The reaction mixture was stirred for 15 min then allowed to warm to 0° C. A solution of diazomethane (prepared according to the standard procedure (Organic Syntheses, Coll. Vol. 5, p. 351 (1973); Vol. 41, p. 16 (1961)) in Et2O (150 mL) was added, until the rich yellow color persisted. The reaction mixture was allowed to warm to rt and stirred for 3 h. Excess CH2N2 was destroyed by the addition of a small amount of aqueous AcOH (20%, 3 mL). The reaction mixture was extracted with saturated NaHCO3 (20 mL), and the organic portion was separated and washed with saturated aqueous NH4Cl (20 mL) and brine (20 mL). The organic portion was separated, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-20% EtOAc in petroleum ether) to give (3-diazo-1-methyl-2-oxo-propyl)-carbamic acid tert-butyl ester (2.8 g, 99%) as a brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.27 (d, J=7.2, 1H), 6.02 (s, 1H), 4.01 (m, 1H), 1.39 (s, 9H), 1.20 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].CCOCC>O1CCCC1>[Br:18][C:10]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][N:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(-c2cc3cccc(Cl)n3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2Br)cc1
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a cold (0° C.) solution of 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (5.0 g, 20.2 mmol) in tetrahydrofuran (81 mL) was added N-bromosuccinimide (3.79 g, 21.2 mmol) in two portions. The solution solidified after 5 minutes and additional tetrahydrofuran was added (20 mL). The resultant solution was stirred for 15 minutes. Saturated aqueous sodium bicarbonate and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layers were extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by recrystallization from ethyl acetate-hexane-methanol provided 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (5.7 g, 87%) as a crystalline solid. 1H NMR (CDCl3) δ 8.07 (dd, 2H), 7.53 (d, 1H), 7.23–7.16 (m, 3H), 6.98 (d, 1H); 19F NMR (CDCl3) δ −112.60; MS m/z 325 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:22]2[CH2:27][CH2:26][N:25](CCOC)[CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH2:20][CH3:21])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].NC1C=C([C@H](N2CCN([CH2:62][CH2:63][CH2:64][O:65][CH3:66])CC2)C2C=CC(C(N(CC)CC)=O)=CC=2)C=CC=1.C(=O)CC.[B][B][B][B][B][B][B][B][B][B].C(O)(C(F)(F)F)=O>>[CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:22]2[CH2:27][CH2:26][N:25]([CH2:62][CH2:63][CH2:64][O:65][CH3:66])[CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:19][CH2:20][CH3:21])[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(N)c2)N2CCN(CCCOC)CC2)cc1
Reactant: CCCNc1cccc([C@@H](c2ccc(C(=O)N(CC)CC)cc2)N2CCN(CCOC)CC2)c1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CCC=O
Solvent: O=C(O)C(F)(F)F
Product: CCCNc1cccc([C@@H](c2ccc(C(=O)N(CC)CC)cc2)N2CCN(CCCOC)CC2)c1
Yield: 55 %

Procedure:
Using the same method as for COMPOUND 61 and using COMPOUND 60 (86.0 mg, 0.20 mmol), propionaldehyde (0.014 mL, 0.19 mmol) and decaborane (7.2 mg, 0.059 mmol) afforded COMPOUND 62 (89 mg, 55% yield) as its TFA salt. This material was lyophilized from CH3CN/H2O to produce a hygroscopic, slightly yellow solid. Purity (HPLC): >97%; Optical purity (Chiral HPLC): >93%; 1H NMR (400 MHz, CD3OD) δ 1.01 (t, J=7.4 Hz, 3H), 1.09 (br t, J=6.6 Hz, 3H), 1.22 (br t, J=6.6 Hz, 3H), 1.70 (sextet, J=7.6 Hz, 2H), 1.95-2.04 (m, 2H), 2.39 (br s, 2H), 3.01 (br s, 2H), 3.15-3.28 (m, 8H), 3.33 (s, 3H), 3.45-3.61 (m, 6H), 4.55 (s, 1H), 7.10-7.16 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.37-7.44 (m, 3H), 7.57 (d, J=8.0 Hz, 2H). Found: C, 53.22; H, 6.76; N, 7.48. C29H44N4O2×2.0 H2O×2.0 CF3COOH has C, 53.22; H, 6.77; N, 7.52%. [α]D17=−1.5 deg [c 0.779, MeOH].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(Cl)cc1
Yield: 92 %

Procedure:
A solution of 4-chlorobenzylsulfonyl acetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 92% yield.