Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(Br)C=C(F)C=1.[Mg].Cl[C:22]1[N:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:24][N:23]=1.Cl>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[N:23]=[CH:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][N:27]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(Cl)cc([Mg]Br)c1
Reactant: CCCCCc1cnc(Cl)nc1
Agent: Cl
Agent: Fc1cc(Cl)cc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCc1cnc(-c2cc(F)cc(Cl)c2)nc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A solution of 3-chloro-5-fluorophenylmagnesium bromide [prepared from 22.7 g (108.3 mmol) of 3-chloro-5-fluoro-bromobenzene and 2.7 g (111.0 mmol) of magnesium, and 100 ml of diethyl ether] in diethyl ether was added by drops to a mixture of 10 g (54.1 mmol) of 2-chloro-5-pentylpyrimidine, 0.4 g (0.5 mmol) of dichloro[1,1′-bis(diphenylphosphino) ferrrocene]palladium, and 300 ml of diethyl ether while being maintained at a temperature lower than −60° C., stirred at the same temperature for 1 hour, and then stirred at 10° C. for 10 hours. A diluted hydrochloric acid in an amount of 300 ml was added to the reaction mixture and extracted with 250 ml of heptane. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=1/1) to obtain 11.0 g of a crude 2-(3-chloro-5-fluorophenyl)-5-pentylpyrimidine. (Yield: 72.8%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:23]([C:22]([O:29][CH3:30])=[O:28])[C:24]([O:26][CH3:27])=[O:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][O:20][CH3:21])=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)CC(=O)OC
Product: COCOc1ccc(C(=O)CC(c2ccc(Cl)cc2)C(C(=O)OC)C(=O)OC)cc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 3-(4-chlorophenyl)-1-(4-methoxymethoxy-phenyl)prop-2-en-1-one and dimethyl malonate, dimethyl 2-(1-(4-chlorophenyl)-3-(4-(methoxymethoxy)phenyl)-3-oxopropyl)malonate was obtained as colourless solid.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5]C=CC=2)[CH:3]=C1C(O)=O.[Br:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:23]([OH:25])=[O:24].C(OC(OC(C)(C)C)N(C)C)(C)(C)C>C1(C)C=CC=CC=1>[Br:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]=1[C:23]([O:25][C:4]([CH3:9])([CH3:5])[CH3:3])=[O:24]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(O)c1[nH]c2ccccc2c1Br
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1[nH]c2ccccc2c1Br
Temperature: 90 °C

Procedure:
Indole-2-carboxylic acid was converted to 3-bromoindole-2-carboxylic acid using the method described for Example 13. N,N-dimethylformamide di-tert-butyl acetal (35 mL) was added dropwise to a stirring mixture of indole-3-bromo-2-carboxylic acid (14.9 g, 62 mmol) suspended in toluene (100 mL). After the addition was complete, the reaction was heated at 90° C. for 8 h. The reaction mixture was then cooled to room temperature and washed with cold water (2×100 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude tert-butyl 3-bromoindole-2-carboxylate, assume quantitative yield. The crude product was used in the next step without purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O.CO>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(C(=O)OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(C(=O)O)cc1
Yield: 65.8 %

Procedure:
2-n-Butyl-1-(4-carbomethoxybenzyl)-4-chloro-5-(methoxymethyl)imidazole (15.2 g, 43.3 mmol, 1 eq), 0.5 N KOH in methanol (130 mL, 65.0 mmol, 1.5 eq), water (10 mL) and methanol (50 mL) were mixed and refluxed for 4 hours. The solvent was removed in vacuo and the residue dissolved in water (300 mL). The pH was adjusted to 4 with conc. HCl and this aqueous mixture extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried (MgSO4), the solved removed in vacuo and the crude residue recrystallized from hexane/butyl chloride to yield 9.6 g of white solid; m.p. 126.5°-127.5°. NMR (200 MHz, DMSO-d6) δ 12.95 (bs, 1H); 7.93 (d, 2H, J=9 Hz); 7.16 (d, 2H, J=9 Hz); 5.30 (s, 2H); 4.31 (s, 2H); 3.19 (s, 3H); 2.50 (t, 2H, J=7 Hz); 1.49 (t of t, 2H, J=7,7 Hz); 1.24 (t of q, 2H, J=7,7 Hz); 0.80 (t, 3H, J=7 Hz). Anal. Calcd. for C17H21ClN2O3 : C, 60.62; H, 6.29; N, 8.32. Found: C, 60.89; H, 6.10; N, 8.03.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:11]=[C:10]([CH:37]=[O:38])[N:9]=1)(=[O:3])[CH3:2].C1CC2[O:45]CCOCCOC3C(OCCOCCOC2CC1)CCCC3.[Mn]([O-])(=O)(=O)=O.[K+]>C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:12]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[N:11]=[C:10]([C:37]([OH:45])=[O:38])[N:9]=1)(=[O:3])[CH3:2]
Reactant: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C=O)nc2OCCOC(C)=O)c1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)nc(C(=O)O)nc2OCCOC(C)=O)c1
Yield: 32.4 %

Procedure:
0.27 g of 2-[6-(4-tert.butyl-phenylsulphonylamino)-2-formyl-5-(3-methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl acetate and 0.19 g of dicyclohexyl-18-crown-6 in 15 ml of benzene were stirred with 0.078 g of potassium permanganate at 2000 for 16 hours. The reaction mixture was partitioned between toluene and water. The organic phase was dried and evaporated, and the residue was purified over silica gel with chloroform-methanol. 0.09 g of 4-(2-acetoxy-ethoxy)-6-(4-tert.butyl-phenylsulphonylamino)-5-(3-methoxy-phenoxy)-pyrimidine-2-carboxylic acid was obtained as a foam, MS: (M-H)- 558.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[CH2:13][S:12]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:35][N+:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[S:38][C:37]=1SC>>[C:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:14](=[O:23])[C:13](=[C:37]3[N:36]([CH3:35])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[S:38]3)[S:12]2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CSc1sc2ccccc2[n+]1C
Reactant: CC(=O)c1cccc(N=C2SCC(=O)N2Cc2cccnc2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)c1cccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2cccnc2)c1

Procedure:
The title compound was prepared from intermediate 2-(3-acetylphenylimino)-3-pyridin-3-ylmethylthiazolidin-4-one and 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate as described in Example 45. 1H-NMR (CDCl3): δ 8.87 (1H, d), 8.56 (1H, dd), 7.93 (1H, m), 7.74 (1H, m), 7.60 (1H, m), 7.53 (1H, d), 7.46 (1H, m), 7.27–7.38 (2H, m), 7.17–7.23 (2H, m), 7.05 (1H, d), 5.18 (2H, s), 3.74 (3H, s), 2.62 (3H, s); MS(ESI): 473 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][F:29].O>C(Cl)(Cl)Cl>[F:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: FCCCBr
Reactant: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
242 mg (corresponding to 1.0 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine that was sufficiently dried to remove moisture was dissolved in 10 L of N,N-dimethylformamide, and 418 mg (corresponding to 3.0 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 140 μL (corresponding to 1.5 mmol) of 1-bromo-3-fluoropropane, and then was stirred at room temperature for 18 hours. After the completion of the reaction, the reaction solution was poured into water and extracted three times with chloroform. The combined chloroform layer was washed once with water and once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name: manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 189 mg (corresponding to 0.63 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-methoxyimidazo[1,2-a]pyridine (hereinafter referred to as Compound 1) (FIG. 2, Step 6).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[CH2:34]1[C@@H:38]2[CH2:39][CH2:40][CH:41]([OH:42])[C@@H:37]2[CH2:36][NH:35]1.C(N(CC)CC)C>CN(C=O)C>[OH:42][CH:41]1[C@@H:37]2[CH2:36][N:35]([C:2]3[N:3]=[C:4]([C:23]4[O:24][C:25]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:26][N:27]=4)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=3)[CH2:34][C@@H:38]2[CH2:39][CH2:40]1
Reactant: OC1CC[C@H]2CNC[C@@H]12
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2C[C@@H]3CCC(O)[C@@H]3C2)nc1-c1nnc(-c2ccccc2)o1
Yield: 83.7 %

Procedure:
A solution of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (115 mg, 0.22 mmol), (3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-ol (73 mg, 0.57 mmol) and triethyl amine (34 mg, 46 μL, 0.33 mmol) in DMF was heated to 90° C. for 90 minutes. The solvent was removed under reduced pressure and the crude material was purified by silica gel column chromatography using 5-60% EtOAc in DCM to yield tert-butyl N-[5-[(3aR,6aS)-6-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (104 mg, 83%). LC/MS m/z 465.5 [M+H-Boc]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:27])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:27])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: CCOC(=O)c1sc(Br)cc1C
Product: CCOC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)cc1C
Yield: 26 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with ethyl 5-bromo-3-methylthiophene-2-carboxylate in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 26% yield: 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=7.8 Hz, 1H), 7.44-7.36 (m, 5H), 6.87 (s, 1H), 6.13 (dd, J=7.8, 2.7 Hz, 1H), 6.07 (d, J=2.7 Hz, 1H), 5.04 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 370.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:26])([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:5][C:4]=1[NH2:27].[C:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH2:37][C:38](O)=O)=[CH:32][CH:31]=1)#[N:29].C(N1C=CN=C1)(N1C=CN=C1)=O>C(O)(=O)C>[C:28]([C:30]1[CH:31]=[CH:32][C:33]([NH:36][CH2:37][C:38]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][C:6]([C:9]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:10]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)=[O:11])[CH3:26])=[CH:5][C:4]=3[N:27]=2)=[CH:34][CH:35]=1)#[N:29]
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N2CCCC2)cc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(C)(CNC(=O)OC(C)(C)C)C(=O)N3CCCC3)ccc21

Procedure:
Prepared analogously to Example 1g/h from 2-[4-(N-methylamino)-3-amino-phenyl]-2-methyl-3-(tert.butyloxycarbonylamino)-1-pyrrolidino-propan-1-one, 4-cyano-phenylglycine/carbonyldiimidazole and subsequent treatment with glacial acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.C(#N)C.[Br:22]N1C(=O)CCC1=O>>[Br:22][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)=[CH:8]2
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[C@@]1(c2ccc3c(Br)c(O)ccc3c2)COC(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (Example 4, 5.05 g, 20.8 mmol) was suspended in acetonitrile (50 mL, 1000 mmol) in a capped 200 mL round-bottom flask equipped with a magnetic stir bar. The mixture was cooled to 0° C. and N-bromosuccinimide (3.88 g, 21.8 mmol) was added. The reaction mixture was stirred for 1 hour. HPLC analysis indicated that the reaction was complete. The mixture was filtered. The residue was rinsed with acetonitrile, air dried under vacuum and collected (5.54 g). The crude product required no purification (82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:30][C:31]([C@@H:33]2[CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][N:34]2C(OC(C)(C)C)=O)=[O:32])[C:10](=[O:29])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl>CCOC(C)=O>[CH2:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:42][C@@H:33]([C:31]([NH:30][C@H:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10](=[O:29])[N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:23]3[CH:27]=[CH:26][NH:25][C:24]3=[O:28])[CH2:13][CH2:12]2)=[O:32])[NH:34]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2-n2cc[nH]c2=O)CC1)[C@@H]1Cc2ccccc2CN1
Yield: 58.4 %

Procedure:
The title compound was prepared according to the procedure described in Example 10 (Step c) from tert-butyl (3S)-3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-oxo-2-(4-[2-(2-oxo(4-imidazolinyl))phenyl]piperidyl)ethyl) carbamoyl]-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step c) (0.3 g, 0.44 mmol) and satd anhydrous HCl in EtOAc (20 mL). Recrystallization from 1:20 MeOH:Et2O provided the title compound (HCl salt) as a white solid (0.15 g). MP 191° C. (decomposed). MS (ESI, pos. ion) m/z: 584 (M+1). Calc'd for C33H34ClN5O3: 597.25. Anal. Calcd for C33H34ClN5O3HCl.2.25H2O: C, 59.95; H, 6.02: N, 10.59; Cl, 10.13. Found: C, 59.93; H, 5.83; N, 10.45; Cl, 10.57.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[Cl:8][C:9]1[CH:10]=[N:11][C:12](=[O:15])[NH:13][CH:14]=1.Br[CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][CH2:17][N:11]2[CH:10]=[C:9]([Cl:8])[CH:14]=[N:13][C:12]2=[O:15])=[CH:20][CH:21]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Clc1ccc(SCBr)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CSc1ccc(Cl)cc1

Procedure:
Potassium tert-butoxide (40 mmol) in DMF (25 ml) was added to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in DMF (125 ml). The mixture was stirred at room temperature for 15 min before 1-bromomethylsulfenyl-4-chlorobenzene [see U.S. Pat. No. 2,827,492; Chem. Abstract 52 Pl 6296 d (1958)](25 mmol) was added. The resultant mixture was stirred at room temperature at 60° C. for 3h, the solvent removed at reduced pressure and the residue triturated with water and dried. The residual product was a mixture of the N- and O-alkylated isomers in the ratio 3:1 (1H NMR); yield 4.2 g (73%). The isomers were separated by their different solubilities in acetone, the less polar O-isomer being the more soluble isomer. The title compound, the N- isomer had m.p. 191° C. (acetone). (Found C45.90; H2.78. Calc. for C11H8Cl2N2OS: C46.00; H2.81) 1 H NMR (CDCl3): δ 5.25 (CH2), 7.35 (Ph, s), 8.20 and 8.50 (H-4, H-6, d, J 4 Hz). IR (KBr): 1660 cm-1 (CO). MS (70 eV; m/z (% rel. int)): 286 (4, M), 157 (11), 156 (11), 145 (33), 143 (100), 116 (27).
Reaction SMILES: C1(CN2CCC(C[CH2:15][C:16]3[C:20]4[CH:21]=[CH:22][C:23]5[NH:27][C:26](=[O:28])[CH2:25][C:24]=5[C:19]=4[O:18][N:17]=3)CC2)C=CC=CC=1.N1C=CC=CC=1>CN(C=O)C>[CH3:15][C:16]1[C:20]2[CH:21]=[CH:22][C:23]3[NH:27][C:26](=[O:28])[CH2:25][C:24]=3[C:19]=2[O:18][N:17]=1
Reactant: O=C1Cc2c(ccc3c(CCC4CCN(Cc5ccccc5)CC4)noc23)N1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1noc2c3c(ccc12)NC(=O)C3
Yield: 33.9 %

Procedure:
The procedure described in Example 33d was followed with the oxime acetate obtained in step c (0.334 g, 1.35 mmol) and pyridine (0.55 mL, 6.75 mmol) in DMF (25 mL). After work-up, the residue was purified by silica gel flash chromatography (50→75% EtOAc-hexanes) to give the title compound (0.086 g, 34%) as a white solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=O.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN)(=O)=O)(C)C.[C-:30]#[N:31].[K+]>CO>[C:30]([CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)#[N:31]
Reactant: [C-]#N
Reactant: O=C1CC2CCN1CC2
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN)c(C(C)C)c1
Agent: [K+]
Solvent: CO
Product: N#CC1CN2CCC1CC2
Yield: 23.6 %

Procedure:
Quinuclidinone (24.2 g, 0.19 mol) and 2,4,6-triisopropylbenzene sulphonohydrazide (72 g, 0.24 mol) (250 ml) were stirred together in anhydrous methanol for 3 hours. Potassium cyanide (33.8 g, 0.51 mol) was added and the mixture heated under reflux for 5 hours. The material isolated, after evaporation of the solvent, was partitioned between water and dichloromethane. The organic phase was dried (sodium sulphate) and evaporated and the residue fractionally distilled under reduced pressure to give 3-cyano-quinuclidine (6.1 g), approximate b.p. 95°-100° at 13 N.m-2 (0.1 mmHg).
Reaction SMILES: [C:1]([CH:3]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[N:2].[NH2:26][OH:27]>CO>[NH2:2]/[C:1](=[N:26]\[OH:27])/[CH:3]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:4][CH2:5][C:6]([CH3:16])([CH3:15])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: NO
Reactant: CN(C(=O)OC(C)(C)C)C(C#N)CCC(C)(C)COC1CCCCO1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(CCC(C)(C)COC1CCCCO1)/C(N)=N/O
Temperature: 60 °C

Procedure:
To a stirred solution of tert-butyl [1-cyano-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]methylcarbamate (8.5 g, 23.98 mmol), in methanol (5 mL) was added 50% hydroxylamine (1.543 mL, 25.2 mmol). The mixture was heated to 60° C. for 3 hours (LC-MS indicates complete conversion) cooled and concentrated. Removal of excess hydroxylamine azeotropically with methanol gave tert-butyl [1-[(Z)-amino(hydroxyimino)methyl]-4,4-dimethyl-5-(tetrahydro-2H-pyran-2-yloxy)pentyl]methylcarbamate: MS (ES+): 388.26 (M+H).
Reaction SMILES: [CH2:1]([CH:4]1[C:9]2[C:10](=[O:15])[CH:11]=[CH:12][C:13](=[O:14])[C:8]=2[CH2:7][CH:6]([C:16]([O:18][CH3:19])=[O:17])[O:5]1)[CH2:2][CH3:3].O([CH:24]=[CH:25][CH:26]=[CH2:27])C(C)=O>>[CH2:1]([CH:4]1[C:9]2[C:10](=[O:15])[C:11]3[C:12]([C:13](=[O:14])[C:8]=2[CH2:7][CH:6]([C:16]([O:18][CH3:19])=[O:17])[O:5]1)=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:2][CH3:3]
Reactant: CCCC1OC(C(=O)OC)CC2=C1C(=O)C=CC2=O
Reactant: C=CC=COC(C)=O
Product: CCCC1OC(C(=O)OC)CC2=C1C(=O)c1ccccc1C2=O
Yield: 71.9 %

Procedure:
The 1-propyl-3-methoxycarbonyl-3,4,5,8-tetrahydro-5,8-dioxo-1H-benzo-[2,3-c]-pyran described in step 3 (76 mg, 0.288 mmol) was stirred with 1-acetoxyl-1,3-butadiene (136 μl, 1.152 mmol) at 45° C. for 20 hours. Solvent was evaporated and the crude product was chromatographed (toluene/ethyl acetate ~100/15, v/v) to give the titled compound (65 mg, 71.9%).
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[C:12]([O:17][CH3:18])=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:21]1[N:26]=[C:25]([N:27]([CH3:40])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:39])[CH3:38])(=[O:36])=[O:35])[C:24]([Cl:41])=[CH:23][N:22]=1>>[Cl:41][C:24]1[C:25]([N:27]([CH3:40])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH:37]([CH3:38])[CH3:39])(=[O:36])=[O:35])=[N:26][C:21]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:19])[F:1])[CH2:11][CH2:10][C:9]=3[C:12]=2[O:17][CH3:18])=[N:22][CH:23]=1
Reactant: COc1c(N)ccc2c1CCC(NCC(F)F)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1N(C)c1nc(Cl)ncc1Cl
Product: COc1c(Nc2ncc(Cl)c(N(C)c3ccccc3S(=O)(=O)C(C)C)n2)ccc2c1CCC(NCC(F)F)CC2
Yield: 4.4 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-methyl-[2-(propane-2-sulfonyl)-phenyl]-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-1-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-methyl-N*4*-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (4.71 mg, 4.4% yield) as a brown oil. 1H-NMR (CDCl3) δ 9.57 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.65 (m, 1H), 7.47 (s, 1H), 7.27 (m, 1H), 6.83 (d, J=7.8 Hz, 1H), 5.83 (m, 1H), 3.73 (m, 3H), 3.22 (m, 2H), 3.02 (m, 2H), 2.83 (m, 2H), 2.67 (m, 1H), 2.49 (m, 1H), 2.11 (m, 2H), 1.32 (m, 10H). LC/MS (ESI+)=580 (M+H).