Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][CH2:18][C@H:17]3[C@@H:8]([CH2:9][CH2:10][C:11]4[C@@H:16]3[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=4)[C@@H:7]1[CH:6]=[CH:5][C:4]2=[O:21].[C-:22]#[C-:23].[Li+].[Li+]>>[CH3:1][CH2:2][C@@:3]12[C@:4]([OH:21])([C:22]#[CH:23])[CH:5]=[CH:6][C@H:7]1[C@@H:8]1[CH2:9][CH2:10][C:11]3[C@@H:16]([C@H:17]1[CH2:18][CH2:19]2)[CH2:15][CH2:14][C:13](=[O:20])[CH:12]=3
Reactant: [C-]#[C-]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Agent: [Li+]
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Yield: 75 %

Procedure:
By treating 18-methyl-4,15-estradiene-3,17-dione (Formula III: Y=O, A-B=CH=CH) with lithium acetylide, gestodene is obtained in a high yield of about 75%. However, this method is usable only for amounts of starting material compounds up to 100 g; ethynylation in this manner therefore cannot be performed on an industrial scale. Moreover, it has been found that the 18-methyl-4,15-estradiene-3,17-dione starting material can have a sensitizing effect in case of skin contact, consequently protective measures must be observed when handling 18-methyl-4,15-estradiene-3,17-dione.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[F:36]>>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:27][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=2[F:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Oc1ccccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: N#Cc1ccc(CBr)c(F)c1
Product: N#Cc1ccc(COc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol and 4-bromomethyl-3-fluoro-benzonitrile (105942-09-4). Brown sticky solid (69%). MS (Turbo Spray): m/z=476.4 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]1[CH2:37][CH2:36][N:11]2[C:12]3[C:17]([C:18]([C:19]4[C:20](=[O:35])[NH:21][C:22](=[O:34])[C:23]=4[C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C)C=O>[N:38]([CH2:6][CH2:7][CH:8]1[CH2:37][CH2:36][N:11]2[C:12]3[C:17]([C:18]([C:19]4[C:20](=[O:35])[NH:21][C:22](=[O:34])[C:23]=4[C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]([CH3:33])[CH:25]=4)=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N+:39]=[N-:40]
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CCOS(C)(=O)=O)C4)C(=O)NC2=O)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CCN=[N+]=[N-])C4)C(=O)NC2=O)c2ccccc21
Yield: 94.7 %

Procedure:
A solution of 500 mg of the pyrroledione product of Example 15 and 250 mg of sodium azide in 10 ml of dimethylformamide was heated at 70° C. for 3 hours. The solvent was removed by evaporation and the solid was partitioned between ethyl acetate and water. The insoluble material was filtered off and dried to give 425 mg of 3-[8-(2-azidoethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 262°-264° C.
Reaction SMILES: [CH2:1]([S:21][CH:22]([CH2:28][CH3:29])[C:23]([O:25]CC)=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[Li+].[OH-].Cl>C(O)C.O>[CH2:1]([S:21][CH:22]([CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(CC)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCSC(CC)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
Ethyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenylthio)butanoate (209 mg, 0.50 mmol) was dissolved in ethanol (2.5 mL) and added to a solution of LiOH×H2O (168 mg, 4.0 mmol) in water (2.5 mL). The resulting turbid solution was stirred at 70° C. under inert atmosphere for 2 hours, cooled and added water (10 mL) and 1 M HCl (5 mL) to pH=1-2. The mixture was extracted with heptane (2×20 mL) and diethyl ether (20 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to give 154 mg of the title compound as crude oil. Purification by flash chromatography on silica gel using gradient elution (starting with pure heptane and increasing stepwise to heptane:EtOAc (with 5% HOAc) 80:20) afforded 151 mg (77% yield) of the title compound as oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[C:16]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[CH:4]([CH:7]=[CH:23][C:16](=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH:2]1[OH:1]
Reactant: O=CC1CCC(O)C1CCCCCCO
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CCC(O)C1CCCCCCO
Yield: 64.2 %

Procedure:
A mixture of 3-hydroxy-2-(6-hydroxyhexyl)cyclopentanecarbaldehyde (8.6 g.) and hexanoylmethylene triphenylphosphorane (16 g., 0.043 mole) in dry tetrahydrofuran (100 ml.) was heated under reflux for 6 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel. Elution with a 3:2 mixture of petrol (b.p. 40°-60°C.) and ethyl acetate gave 2-(6-hydroxyhexyl)-3-(3-oxo-1-octenyl)cyclopentanol (8 g.), νmax 1660 cm-1, 1620 cm-1 (liquid film).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[C:13]([OH:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH3:16])[N:9]=2)[S:5][C:6]=1[CH3:7].[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C1C=CN=CC=1.CS(C)=O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:14][C:13]3[C:8]([C:4]4[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=4)=[N:9][C:10]([CH3:16])=[C:11]([CH3:15])[CH:12]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cc(O)c(-c2nc(C)c(C)s2)nc1C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3nc(C)c(C)s3)ccnc2cc1OCc1ccccc1
Temperature: 130 °C
Reaction time: 9 h
Yield: 22.1 %

Procedure:
2-(4,5-Dimethyl-thiazol-2-yl)-5,6-dimethyl-pyridin-3-ol (200 mg), 7-benzyloxy-4-chloro-6-methoxyquinoline (768 mg), 4-dimethylaminopyridine (313 mg), and cesium carbonate (313 mg) were suspended in dimethyl sulfoxide (4 ml), and the mixture was stirred at 130° C. for 9 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (94 mg, yield 22%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[CH:38]1([NH:41][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NC1CC1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclopropylamine according to conditions described in general procedure C. Mp: 157-158° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.32-0.48 (m, 4 H), 1.58 (s, 6 H), 3.19-3.31 (m, 4 H), 6.34 (bs, 1 H), 6.96 (d, J=12.4, 1 H), 7.15 (d, J=8.7 Hz, 1 H), 7.34-7.42 (m, 3 H), 7.53-7.63 (m, 3 H), 7.81 (d, J=8.0 Hz, 1 H), 7.95 (d, J=8.0 Hz, 1 H), 8.21-8.23 (m, 1 H), 10.40 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:9][C:8]2=[O:23])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[Br:33][C:9]1[C:8](=[O:23])[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)[C:12]([CH3:13])=[CH:11][C:10]=1[NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: Cc1cc(NCc2ccc(F)cc2)cc(=O)n1Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1cc(NCc2ccc(F)cc2)c(Br)c(=O)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one (0.2857 g, 0.84 mmol) in MeCl2 was added NBS (0.156 g, 0.88 mmol). The reaction stirred at room temperature under nitrogen for 45 minutes. The reaction mixture was diluted with MeCl2 and washed with NaHCO3. The organic extracts were washed with water, dried over Na2SO4, and concentrated to afford the desired product (0.3242 g, 92%) as a yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.32 (q, 2H), 7.04 (m, 6H), 5.91 (s, 1H), 5.28 (s, 2H), 4.50 (s, 2H), 2.17 (s, 3H); ES-HRMS m/z 419.0549/421.0537 (M+H calculated for C20H18N2OBrF2 requires 419.0565/421.0547).
Reaction SMILES: Cl.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.[F:43][C:44]1[CH:71]=[C:70]([N+:72]([O-])=O)[CH:69]=[CH:68][C:45]=1[O:46][C:47]1[C:52]2=[C:53]([CH3:67])[C:54]([C:56]([NH:58][CH2:59][CH2:60][N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[O:57])=[CH:55][N:51]2[N:50]=[CH:49][N:48]=1>>[NH2:72][C:70]1[CH:69]=[CH:68][C:45]([O:46][C:47]2[C:52]3=[C:53]([CH3:67])[C:54]([C:56]([NH:58][CH2:59][CH2:60][N:61]4[CH2:66][CH2:65][O:64][CH2:63][CH2:62]4)=[O:57])=[CH:55][N:51]3[N:50]=[CH:49][N:48]=2)=[C:44]([F:43])[CH:71]=1
Reactant: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 92.3 %

Procedure:
Following a procedure similar to that for the synthesis of Compound C of Example 36, 4-(2-fluoro-4-nitrophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (75 mg, 0.17 mmol) was converted to the title compound (65 mg, 92%). LCMS(ESI+) m/z 415.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][OH:22])[C:18]([CH3:24])([CH3:23])[C:17]3=[O:25])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6].Cl[C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:3][O:4][C:5]([CH:7]1[CH2:14][CH:13]2[CH:15]([N:16]3[CH2:20][CH:19]([CH2:21][O:22][C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=4)[C:18]([CH3:23])([CH3:24])[C:17]3=[O:25])[CH:9]([CH2:10][CH2:11][CH2:12]2)[CH2:8]1)=[O:6]
Reactant: COC(=O)C1CC2CCCC(C1)C2N1CC(CO)C(C)(C)C1=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C1CC2CCCC(C1)C2N1CC(COc2ccc(C#N)cn2)C(C)(C)C1=O
Temperature: 25 °C

Procedure:
NaH (0.1 g, 60% in oil, 2.56 mmol) was added in one portion to a stirred and cooled (0° C.) solution of the product of Example 7D (0.48 g, 1.42 mmol) and 6-chloro-nicotinonitrile (0.35 g, 2.56 mmol) in tetrahydrofuran (7 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (7 mL). After the addition, the solution was warmed to room temperature and stirred for another five hours. The dark brown reaction mixture was cooled (0° C.), quenched with acetic acid (0.1 mL), and partitioned with diethyl ether and water. The organic phase was washed with water and brine, dried (MgSO4), filtered, and evaporated. The residue was purified over silica gel using 5-80% ethyl acetate in hexanes to give the titled product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:29]([N:31]([C@@H:43]([CH3:51])[CH:44]([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([NH:19][C@H:20]([C:29]([N:31]([C@@H:43]([CH3:51])[CH:44]([O:48][CH2:49][CH3:50])[O:45][CH2:46][CH3:47])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[C:37]3[C:42]=2[N:41]=[CH:40][CH:39]=[CH:38]3)=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[O:16])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 89 mg (0.33 mmol) was coupled with (S)-tert-butyl 3-amino-4-(((S)-1,1-diethoxypropan-2-yl)-(quinolin-8-ylmethyl)amino)-4-oxobutanoate (Compound IV-17) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.[C:9]([O:12][C@@H:13]1[N:16]([S:17]([OH:20])(=[O:19])=[O:18])[C:15](=[O:21])[C@H:14]1[NH2:22])(=[O:11])[CH3:10].[Na+:23].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>C1COCC1.O>[C:9]([O:12][C@@H:13]1[N:16]([S:17]([O-:20])(=[O:19])=[O:18])[C:15](=[O:21])[C@H:14]1[NH:22][C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:11])[CH3:10].[Na+:23]
Reactant: CC(=O)O[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Reaction time: 1.5 h

Procedure:
To a solution of 0.61 g of acetate of sodium (3S,4S)-4-acetoxy-3-amino-2-oxoazetidine-1-sulfonate obtained in Example 21B in 20 ml of a mixture of water and THF(1:1) is added under ice-cooling 0.61 g of phenylacetyl chloride while keeping the pH of the reaction mixture at pH 7.0-7.5 by use of sodium hydrogen carbonate. The stirring is continued for 1.5 hours at the same temperature. THF is removed by evaporation under reduced pressure. The residue is purified on an XAD-II (Rohm and Haas Co.) column chromatography to give 0.42 g of sodium (3S,4S)-4-acetoxy-3-phenylacetamido-2-oxoazetidine-1-sulfonate. The IR spectrum and NMR data of this compound are in agreement with those of the compound obtained in Example 19B.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.I[C:28]1[N:29]=[C:30]([CH3:33])[NH:31][CH:32]=1.C[Si]([C:38]#[C:39][C:40]1[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][C:30]1[NH:31][CH:32]=[C:28]([C:38]#[C:39][C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]#[N:47])[CH:41]=2)[N:29]=1
Reactant: C[Si](C)(C)C#Cc1ccnc(C#N)c1
Reactant: Cc1nc(I)c[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2ccnc(C#N)c2)c[nH]1
Temperature: 60 °C

Procedure:
Triphenylphosphine (126 mg, 0.48 mmol), bis(triphenylphosphine)palladium(II) chloride (1.01 g, 1.44 mmol) and triethylamine (3.65 g, 101.2 mmol) were dissolved in 40 ml of dry THF. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. 4-iodo-2-methyl-1H-imidazole [Tetrahedron Letters 30(11), 1409 (1989)] (5.0 g, 20.8 mmol), 4-trimethylsilanylethynyl-pyridine-2-carbonitrile (4.43 g, 22.1 mmol) and copper (I) iodide (46 mg, 0.24 mmol) were added and the mixture was warmed to 60° C. A 1M solution of tetrabutylammonium fluoride (24 ml, 24.0 mmol) was added dropwise over a period of 30 min. After the addition was finished, the reaction mixture was stirred at 60° C. for another hour. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (methanol/methylene chloride 5:95). The desired product was obtained as a light yellow solid (1.06 g, 21%). MS: m/e=208.9 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>CN(C)C=O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:11][CH:10]=1
Reactant: OC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine and 0.55 g (0.0022 mol) of 4-bromobenzyl bromide were dissolved in 5 ml of dimethylformamide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with sat. bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.54 g (100%) of 1-(4-bromo-benzyl)-piperidin-4-ol was obtained as a colorless oil. MS: me/e (% basic peak)=271, 269 (C12H16BrNO30 , 73, 76), 270, 268 (79, 70), 171, 169 (99, 100), 114 (64), 100 (60).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:21]O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(N(CC)CC)C.O>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]2[N:21]=1
Reactant: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1Cl
Agent: Cl[Fe]Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: Fc1ccc(-c2cc3ccc(C(F)(F)F)cn3n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
To a suspension of 1-(2-chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone oxime (2.65 g, 7.95 mmol) in DME (11 ml) at 5° C. was added TFAA (1.13 ml, 7.95 mmol) and the mixture stirred for 10 minutes. Triethylamine (3.3 ml, 23.85 mmol) was then added dropwise over 15 min. After the addition was complete, the reaction mixture was then warmed to room temperature. After stirring for 1 hour, iron (II) chloride (10 mg) was added and the mixture was then heated to 75° C. for 16 hours then allowed to cool. The mixture was poured into water (100 ml) and extracted with dichloromethane (100 ml). The organic extracts were dried over MgSO4 and concentrated to dryness. This residue was purified by column chromatography on silica gel eluting with diethylether-cyclohexane (1:4). Concentration of the appropriate fractions gave 0.3 g (12%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[C:33]=1[CH3:34].[CH3:35][S:36]([O-:38])=[O:37].[Na+].CNCCNC.CS(C)=O>CCOC(C)=O>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:7]2[C:6]3[C:33]([CH3:34])=[C:2]([S:36]([CH3:35])(=[O:38])=[O:37])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:21])=[O:22])=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1c(S(C)(=O)=O)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 110 °C

Procedure:
A mixture of 8-bromo-6-[(4-tert-butylphenyl)sulfonyl]-7-methyl-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 63, 100 mg, 0.180 mmol) sodium methyl sulfinate (55.2 mg, 0.541 mmol) and copper (II) triflate benzene complex (27.2 mg, 0.054 mmol) was flushed with nitrogen and capped, and was added N,N′-dimethyl ethylenediamine (0.12 mL, 0.108 mmol), and DMSO (0.60 mL). The mixture was heated to 110° C. for 36 h. After cooling to rt, the reaction mixture was diluted with EtOAc, filtered through silica gel, the filtrated was washed with water and brine, and concentrated. The residue was purified by reverse phase HPLC to provide the title compound as a racemic mixture. LC/MS: m/e 553.9 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 7.87 (1H, d), 7.63 (1H, d), 7.19 (2H, d), 7.13 (1H, d), 7.07 (1H, d), 7.02 (2H, d), 5.21 (1H, d), 4.45 (1H, d), 3.15 (3H, s), 2.87 (3H, s), 1.23 (9H, s). The racemic mixture was separated on a Chiracel OD-H column eluting with 20% EtOH in hexanes, at 8.0 mL/min. The faster eluting enantiomer E1 has a retention time of 15.7 min. The slower eluting enantiomer E2 has a retention time of 28.5 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[N:22][CH:23]=1.[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([F:51])[C:37]=1[OH:52]>>[NH2:27][CH2:26][CH2:25][O:24][C:21]1[N:22]=[CH:23][C:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:40]4[CH:39]=[C:38]([F:51])[C:37]([OH:52])=[C:36]([Cl:35])[CH:41]=4)[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: NCCOc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)cn1
Yield: 25.6 %

Procedure:
Following general procedure D, tert-butyl 2-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yloxy)ethylcarbamate (100 mg, 0.19 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.28 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (24 mg, 26% over two steps) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.34-8.24 (m, 2H), 8.13-8.03 (m, 2H), 7.82 (dd, J=8.8, 2.8 Hz, 1H), 7.24-7.10 (m, 3H), 4.65 (t, J 5.1=Hz, 2H), 3.43 (t, J=5.1 Hz, 2H), 2.87-2.81 (m, 1H), 1.23-1.15 (m, 4H); ESI MS m/z 493 [C26H22ClFN4O3+H]+; HPLC>99% (AUC), tR=11.00 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]2([CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]2)[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:23]([OH:26])([CH3:25])[CH3:24]>>[CH:23]([O:26][C:2]([C:4]1([OH:3])[CH2:9][CH2:8][C:7]([CH3:10])=[CH:6][CH2:5]1)([CH3:11])[CH3:1])([CH3:25])[CH3:24]
Reactant: CC(C)O
Reactant: CC1=CCC2(CC1)OC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1=CCC(O)(C(C)(C)OC(C)C)CC1

Procedure:
By procedures similar to those described in Embodiments 57 and 58, 2,2,6-trimethyl-1-oxaspiro(2.5)oct-5-ene was treated with isopropyl alcohol in the presence of p-toluenesulfonic acid to obtain 1-(1-isopropoxy-1-methylethyl)-4-methyl-3-cyclohexen-1-ol. This alcohol was treated with vanadium(IV) bis(2,4-pentanedionate) oxide and tert-butyl hydroperoxide followed by p-toluenesulfonic acid to obtain (±)-2-exo-hydroxy-4-(1-isopropoxy-1-methylethyl)-1-methyl-7-oxabicyclo[2.2.1]heptane. This intermediate was treated with benzyl chloride to yield the desired product, b.p. 120°-130° C. (0.2 mm).