Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[CH:7]1)[CH3:2].C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[CH:7]1)=[CH:16][N:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CCOC(=O)Cn1cnc(C)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cnc(C)c1

Procedure:
310 mg (1.5 mmol, 80% purity) of the compound from Example 34A and 0.5 ml (434 mg, 3.0 mmol) dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For working up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried in vacuo. The product is obtained as a 3:2 mixture of the two regioisomers and is further reacted as such.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]2[S:41][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(=O)NNC(=O)c2ccc(N3CCC(N(C)C)C3)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nnc(-c3ccc(N4CCC(N(C)C)C4)cc3)s2)cc1

Procedure:
A mixture of N′-(4-butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (100 mg), Lawesson's reagent (191 mg) and toluene (5 ml) was boiled under reflux for 4 hours. Volatiles were removed, and the residue was purified by preparative HPLC. The product with the molecular weight of 422.60 (C24H30N4OS) was obtained in this way; MS (ESI): 423 (M+H+).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:5]1.O=S(Cl)[Cl:17]>>[Cl:17][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[N:5]1
Reactant: OCCn1ccc(-c2ccncc2)n1
Reactant: O=S(Cl)Cl
Product: ClCCn1ccc(-c2ccncc2)n1

Procedure:
C] 1-(2-Chloroethyl)-3-(4-pyridinyl)-1H-pyrazole was prepared according to example 14C from 1-(2-hydroxyethyl)-3-(4-pyridinyl)-1H-pyrazole by treatment with SOCl2. MS (EI): 207.1 (M+). 1H-NMR (DMSO-d6): 4,06 (t, 2H), 4.53 (t, 2H), 6.92 (d, 1H), 7.76 (m, 2H), 7.93 (d, 1H), 8.58 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].[O:12]1[CH2:15][CH2:14][CH2:13]1.[NH4+].[Cl-]>C1COCC1>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:15][CH2:14][CH2:13][OH:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: C1COC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
(3-Bromopropyl)benzene (20 g) in THF (75 ml) was added dropwise to magnesium (2.43 g) at a rate to maintain gentle reflux. The mixture was stirred for 2 h at RT and oxetane (10 g) was added dropwise. The resulting suspension was stirred at RT for 2 h and at reflux for 16 h and poured into saturated aqueous NH4Cl (100 ml). The mixture was extracted with ER (3×75 ml) and the dried extract was evaporated to leave a yellow oil. Distillation of the oil gave the title compound as a colourless liquid (6.05 g) b.p. 100°-105°/0.4 mmHg. T.l.c. [O] Rf 0.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:8]([C:17](=[O:18])[CH2:16][Cl:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Nc2ccccc2)c1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Product: O=C(CCl)N(c1ccccc1)c1cccc(F)c1

Procedure:
N-(3-Fluorophenyl)aniline (7.02 g, 0.0375 mole) and chloroacetyl chloride (3.3 ml, 0.0412 mole) were refluxed in benzene (50 ml) for 3 hours, then evaporated in vacuo to solids and the solids triturated with pentane and ether to yield purified title product, 8.69 g, m.p. 115°-117°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NCc1ccncc1
Product: Clc1nc(Cl)nc(NCc2ccncc2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 4-aminomethylpyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [N+](C1C=CC(OC(NC2SC(C3C=CC=CC=3)=CN=2)=O)=CC=1)([O-])=O.C1(C2SC(NC(N[N:40]3[CH2:45][CH2:44][N:43]([CH2:46][C:47]([N:49]4[CH2:53][CH2:52][CH2:51][CH2:50]4)=[O:48])[CH2:42][CH2:41]3)=O)=NC=2)C=CC=CC=1>>[N:49]1([C:47]([CH2:46][N:43]2[CH2:42][CH2:41][NH:40][CH2:45][CH2:44]2)=[O:48])[CH2:50][CH2:51][CH2:52][CH2:53]1
Reactant: O=C(Nc1ncc(-c2ccccc2)s1)NN1CCN(CC(=O)N2CCCC2)CC1
Agent: O=C(Nc1ncc(-c2ccccc2)s1)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(CN1CCNCC1)N1CCCC1

Procedure:
In a manner identical to that described above in Scheme 2, from 200 mg (0.59 mmol) of 2-(4-nitrophenoxycarbonyl)amino-5-phenylthiazole and 117 mg (0.59 mmol) of 1-(pyrrolidinocarbonylmethyl)piperazine was obtained 12 as an amorphous white powder after lyophilization. H1 NMR (DMSO-d6): 1.82 (m, 2H), 1.94 (m, 2H), 3.13 (br m, 2H), 3.38 (complex, 6H), 3.52 (br m, 2H), 4.34 (br m, 2H), 7.28 (t, 1H), 7.41 (t, 2H), 7.56 (t, 2H), 7.78 (s, 1H), 10.14 (br s, 1H). High Res. FAB MS: Theo. Mass=400.1802; measured mass=400.1794.
Reaction SMILES: [CH3:1][C@@:2]1([C:8](O)=[O:9])[CH2:6][CH2:5][C:4](=[O:7])[O:3]1.O1CCCC1>O>[OH:9][CH2:8][C@@:2]1([CH3:1])[O:3][C:4](=[O:7])[CH2:5][CH2:6]1
Reactant: C[C@@]1(C(=O)O)CCC(=O)O1
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]1(CO)CCC(=O)O1
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g. (102.7 mmol) of (S)-(-)-2-methyl-5-oxotetrahydro-2-furoic acid mp 84°-87° C.; [α]25D-16.56° in 70 ml. of dry tetrahydrofuran (THF) was added 10.1 ml. (8.1 g.; 106.7 mmol) of borane-methyl sulphide complex, dropwise, with stirring over a 0.5 hr. period. Occasional ice-bath cooling was employed to maintain the internal temperature below 30°. After stirring at room temperature for 1.5 hr., the reaction mixture was cautiously decomposed by the dropwise addition of 6.2 ml. of H2O. The mixture was then concentrated under water aspirator pressure and the residue was taken up in ethyl acetate and filtered. The solids were washed thorougly with ethyl acetate and filtered. The solids were washed thorougly with ethyl acetate and the filtrate and washes were combined and concentrated in vacuo giving (S)-(+)-5-(hydroxymethyl)-5-methyldihydro-2(3H)-furanone as a colorless oil (13.6 g.) which has used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:28])([CH3:27])[C@@H:11]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:7])=[O:6].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O>[N:29]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:28])([CH3:27])[C@@H:11]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:7])=[O:6])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-methylpropyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (30a) (0.63 g, 1.5 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.22 g (3.0 mmol) of sodium azide (NaN3). After work-up, the crude material (30b) was used in the next step without further purification. MS (ESI) m/z 463.90 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4](F)[CH:3]=1.[SH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].CCN(CC)CC.O>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:11][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CS
Reactant: O=Cc1ccc(Br)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Temperature: 80 °C

Procedure:
To a solution of 4-bromo-2-fluorobenzaldehyde (1.02 g, 4.83 mmol) in DMSO (4 mL), was added ethyl 2-mercaptoacetate (0.58 mL, 5.31 mmol), followed by Et3N (1.35 mL, 9.65 mmol), and the mixture was heated at 80° C. for 3 h. The resulting dark mixture was poured into water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a light yellow waxy solid (1.29 g, 94%).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(C(C)=O)C(C)C>[C:1]([O:4][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CC(=O)CC(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)COC(C)=O
Temperature: 5 °C

Procedure:
A solution of 1.204 l (21.0 moles) of glacial acetic acid and 2.786 l (20.0 moles) of triethylamine in 8.75 l of methyl isobutyl ketone is heated under reflux, and a solution of 1.498 l (11.2 moles) of ethyl 4-chloro-3-oxobutyrate in 1.75 l of methyl isobutyl ketone is added at the boiling point in the course of 20 minutes. When the addition has ended, the mixture is heated under reflux for a further 30 minutes and cooled to about 5° C. and the salts which have precipitated out are filtered off. The residue on the filter is washed with 4.5 l of methyl isobutyl ketone. The combined filtrates are concentrated in vacuo, and first 2 l of drinking water and then 4 l of a 9% strength sodium bicarbonate solution are added to the residue. The suspension is extracted three times with 4 l of ethyl acetate each time and the combined extracts are dried over 2 kg of sodium sulphate, filtered and concentrated in a rotary evaporator at a bath temperature of 40° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Cl:28][C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]1>>[Cl:28][C:29]1[CH:34]=[C:33]([C:15]2[CH:14]=[C:13]([C:5]3[CH:6]=[CH:7][C:8]([C:9]([F:12])([F:11])[F:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=[C:17]([CH3:19])[N:16]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1cc(-c2cc(C)nc(OS(=O)(=O)C(F)(F)F)c2)ccc1C(F)(F)F
Reactant: OB(O)C1(Cl)C=CC=CN1
Product: COc1cc(-c2cc(C)nc(-c3ccnc(Cl)c3)c2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 4-(3-methoxy-4-trifluoromethyl-phenyl)-6-methyl-pyridin-2-yl ester (example A.59) (2.0 g, 5.0 mmol) and commercially available 2-chloropyridine boronic acid (0.758 g, 5.0 mmol) according to the general procedure IVb; Obtained as an off-white solid (1.50 g, 82%). MS (ISP) 379.2 [(M+H)+] and 381 [(M+2+H)+].
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cccc(Cl)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-chloro-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4]/[C:5](=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)/[C:6]2=[O:13]>CO>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1Cl)C/C(=C\c1ccc(SC(F)(F)F)cc1)C2=O
Solvent: CO
Product: COc1ccc2c(c1Cl)CC(Cc1ccc(SC(F)(F)F)cc1)C2=O
Reaction time: 6 h

Procedure:
The (E)-4-chloro-5-methoxy-2-(4-((trifluoromethyl)thio)benzylidene)-2,3-dihydro-1H-inden-1-one 176 (75 mg, 0.195 mmol) was dissolved in methanol 25 ml to which was added Pt/c 40 mg and the reaction stirred under H2 balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude, which was purified by flash chromatography using 100-200 mesh silica gel. The final compound 177 was eluted at 20% ethylacetate in hexane as half white coloured solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.69 (d, 1H), 7.58 (d, 2H), 7.29 (d, 2H), 6.98 (d, 1H), 3.99 (s, 3H), 3.38 (dd, 1H), 3.18 (dd, 1H), 2.99 (m, 1H), 2.73 (m, 1H); MS-ES+386.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15](O)=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1.[Cl-].[NH4+].CC[N:23](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]([NH2:23])=[O:16])=[N:8][C:7]=3[C:6]=2[CH:18]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2.13 g, 6.53 mmol) in THF (22 mL) was added ammonium chloride (1.40 g, 26.1 mmol), DIEA (2.27 mL, 13.1 mmol), and then HATU (2.73 g, 7.18 mmol). The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with sodium bicarbonate and ethyl acetate. The mixture was filtered and the filtrate was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (2.12, quantitative yield). LC/MS (ESI+): m/z 327 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl.C([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH2:58]Cl)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:58][C:54]4[NH:53][CH:57]=[CH:56][N:55]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ncc[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 38.1 using 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine and 1-benzyl-imidazol-2-ylmethylchloride hydrochloride to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10]C)[CH:7]=[C:6]([O:12]C)[C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:12])[C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Br)c(C=O)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)cc(O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 2-bromo-4,6-dimethoxy-benzaldehyde (5.83 g, 23.9 mmol) in dichloromethane (50 mL) was added BBr3 (6.78 mL, 71.7 mmol) at −78° C. The reaction was stirred at room temperature overnight and poured into ice slowly. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=2:1) to give the title compound (4.84 g, 94%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 12.2 (s, 1H), 11.3 (br, 1H), 10.0 (s, 1H), 6.75 (d, J=2.1 Hz, 1H), 6.33 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C>C(#N)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[S:6][C:5]([C:7]#[N:8])=[N:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1nnc(Cl)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C#N)s2)CC1
Yield: 91.1 %

Procedure:
A mixture of 5-chloro-[1,3,4]thiadiazole-2-carbonitrile (0.5 g, 3.44 mmol) (prepared by a procedure similar to that described in U.S. Pat. No. 5,736,545), and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.69 g, 3.44 mmol) and diisopropylethylamine (0.72 ml, 4.13 mmol) in acetonitrile (10 ml) was stirred at 130° C. for 30 min., under microwave irradiation. After this period, the solvent was evaporated in vacuo. The crude product was dissolved in dichloromethane and extracted with a saturated solution of ammonium chloride. The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 3-5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield D5 (0.97 g, 63%) as a white solid. C13H19N5O2S requires 309. Found 308 (MH+).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[N:22][N:23]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[O:20]1[CH:21]=[N:22][N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:14][CH:15]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Brc1ccc(-c2nnco2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ccc(-c3nnco3)cc2)CN2CCC1CC2
Temperature: 65 °C
Yield: 39.2 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (1.06 g), 2-(4-bromopbenyl)-1,3,4-oxadiazole (1.58 g), bis(triphenylphosphine)palladium (II) chloride (245 mg), copper (I) iodide (123 mg), triethylamine (7 ml) and dimethylformamide (14 ml) were heated at 65° C. under an atmosphere of argon for 4 hours. The triethylamine and DHF were removed by evaporation. An aqueous solution of sodium hydroxide (2M, 20 ml) was added to the residue and the mixture extracted with dichloromethane (3×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in dichloromethane containing 1% ammonia (density 0.88 g/cm3) to give 3-[2-(4-[1,3,4-oxadiazol-2-yl]phenyl)ethynyl]-3-hydroxyquinuclidine (811 mg) as a solid, m.p. 229-230%; microanalysis, found: C, 67.9; H, 5.8; N, 14.2%; C17H17N3O3. 0.4 H2O requires: C, 67.5; H, 5.9; N, 13.9; NMR: 1.20-1.44(1H,m), 1.50-1.71(1H,m), 1.77-2.04(3H,m), 2.69(4H,t), 2.79-2.94(1H,d), 3.04-3.20(1H,d), 5.69(1H,s), 7.63(2H,d), 8.03(2H,d), 9.35(1H,s); m/z 296(M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:11])[CH:3]=1.[Li]CCCC.[C:17](=[O:19])=[O:18]>C1COCC1>[Cl:11][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C=O
Reactant: Clc1cc(Br)cc(C2CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(C2CC2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 1-bromo-3-chloro-5-cyclopropylbenzene (300 mg, 1.30 mmol) at −78° C. in THF (5 ml) was added nBuLi (890 μl, 1.6M solution in hexane, 1.43 mmol) dropwise. The resulting solution was stirred at −78° C. for 10 min after which solid carbon dioxide was added and the reaction mixture was warmed to RT over 3 hours. The reaction mixture was quenched with water and then extracted with ether. The aqueous phase was then made acidic with 1N HCl and then extracted with ethyl acetate. The organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the desired product 3-chloro-5-cyclopropylbenzoic acid (178 mg, 70%) which did not require further purification. MS (ISP) 195.1 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=O)(C)(C)C.[H-].[Na+].[CH3:19]I.[ClH:21]>ClCCl.O1CCOCC1>[ClH:21].[CH3:19][O:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CO[C@H]1CN[C@H](C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (25.6 g, 111 mmol), is treated under nitrogen with sodium hydride (9.3 g, 388 mmol) and methyl iodide (31.5 g, 222 mmol), using a procedure similar to that published for the CBZ analog in J. Med. Chem. 1988, 31, 875, except that reflux is carried out for 16 h. The crude extracted product of this alkylation reaction, (2S,4R)-1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-2-carboxylic acid, is then dissolved in dichloromethane (200 mL), cooled to 0° C., treated with 4 N HCl in dioxane (100 mL), and then stirred at room temperature overnight. After further cooling at −20° C. for 3 h, the precipitate is collected by filtration, washed with ethyl ether, and dried in vacuo to give 18.5 g (92%) of the pure mono HCl salt of (2S,4R)-4-methoxypyrrolidine-2-carboxylic acid: MS: 146 (M+H)+; 1H NMR (d6-DMSO) δ 14.02 (brs, 1H), 10.30 (brs, 1H), 8.98 (brs, 1H), 4.33-4.22 (m, 1H), 4.10 (brs, 1H), 3.43-3.34 (m, 1H), 3.24 (s, 3H), 3.26-3.19 (m, 1H), 2.45-2.36 (m, 1H), 2.10-2.00 (m, 1H); [α]22D −29.7 (CH3OH).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20](N)[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.[OH-:25].[NH4+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([OH:25])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: Oc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-pyrimido[5,4-d][2]benzazepine in 20 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 12 hr, and then cooled. After the addition of ice, the reaction mixture was basified with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recrystallized from dichloromethane/methanol to give the end product as white prisms, mp 297°-299° dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol to give additional product.