Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Na].[CH2:3]([C@:6]1([CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[CH2:34][CH2:33]2)[C:11](=[O:12])[O:10][C@@H:9](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[N:7]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:4]=[CH2:5].[Cl-].[NH4+].C[Si](C=[N+]=[N-])(C)C>C1COCC1.CO.CCCCCC.C(O)(=O)C.C(O)C>[C:28]([O:27][C:25]([NH:7][C@@:6]([CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])=[O:39])[CH2:34][CH2:33]1)([C:11]([O:10][CH3:9])=[O:12])[CH2:3][CH:4]=[CH2:5])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: C=CC[C@]1(C2CCN(C(=O)OCC[Si](C)(C)C)CC2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: C=CC[C@@](NC(=O)OC(C)(C)C)(C(=O)OC)C1CCN(C(=O)OCC[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
50 ml of ammonia were condensed at −78° C. 340 mg of sodium were added in 2 portions at an interval of 10 min in each case and the mixture was stirred for 20 min. At −60° C., a solution of 916 mg of tert-butyl (3S,5R,6S)-3-allyl-2-oxo-5,6-diphenyl-3-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-yl]morpholine-4-carboxylate and 866 μl of ethanol in 50 ml of THF was added dropwise. The mixture was stirred at −45° C. for 1.5 h, and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia was then allowed to evaporate off, and 150 ml of water were added to the residue. The THF was removed in vacuo. The aqueous was adjusted to pH 2 with 1 N HCl and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases were dried with MgSO4. The solvents were removed in vacuo, and the residue was filtered through silica gel with 4% methanol in dichloromethane. The product obtained in this way was taken up in 5 ml of methanol and cooled to 0° C. 0.5 ml of a 2 N solution of trimethylsilyldiazomethane in hexane was added thereto 5 times at intervals of 1.5 hours each. 2 ml of acetic acid were then added dropwise, and the mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was chromatographed on silica gel.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)(=[O:1])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)c1ccc(C#N)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)C(=O)c1ccc(C#N)cc1
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 4-(1-hydroxy-2-methylpropyl)benzonitrile (2.500 g, 14.27 mmol) (Prepared according to the method of Keh et al., J. Amer. Chem. Soc., 125(14):4062-4063 (2003)) in dry DCM (200 mL) was added Dess-Martin Periodinane (7.26 g, 17.12 mmol The reaction mixture was stirred for 2 h. The reaction mixture was diluted with DCM and washed with 1N NaOH solution. The organic layer was dried with MgSO4, filtered, and concentrated to yield 2.4 g of 4-isobutyrylbenzonitrile. MS (m+1)=174. HPLC Peak RT=1.60 minutes (Analytical Method B).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([NH:5][CH:6]=[CH:7][C:8]2=O)=[N:3]1.P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>>[Cl:14][C:8]1[C:9]2[C:4](=[N:3][N:2]([CH3:1])[CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Cn1cc2c(=O)cc[nH]c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc2c(Cl)ccnc2n1
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of the product of Example 8b (0.177 g, 1.19 mmol) and phosphorus oxychloride (3 mL) was heated under reflux for 30 min and then cooled to room temperature. The reaction mixture was poured over ice, taken to pH 8 by the addition of 1N aqueous sodium hydroxide solution, and extracted with dichloromethane (3×30 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to provide the title compound (0.170 g, 88% yield).
Reaction SMILES: II.Br[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:10]([N:17]([CH3:31])[C:18]([CH2:20][CH2:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]=[O:30])=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C1COCC1.C1C=CC=CC=1.[Zn]>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH:29]([C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:22](=[O:23])[CH2:21][CH2:20][C:18](=[O:19])[N:17]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:31])[OH:30])[CH3:9]
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1

Procedure:
Zinc powder (482 mg) and a small amount of iodine were added to a solution of ethyl bromoacetate (0.70 ml) in THF (6 ml). The mixture was refluxed for 30 mins. The solution was added dropwise to a solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (1.21 g) in benzene (10 ml). The mixture was refluxed for 30 mins. After reaction, 1N hydrochloric acid was added to the mixture. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (1.21 g) having the following physical data:
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]1[CH:15]2[N:6]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]2=O)[C:5](=[O:17])[CH2:4]1>Cl[Ti](Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][N:2]=[C:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7][N:6]2[C:5](=[O:17])[CH2:4][CH2:3][CH:15]12
Reactant: O=C1c2ccccc2CN2C(=O)CCC12
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CN=C1c2ccccc2CN2C(=O)CCC12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methylamine (1 mL) was condensed at −78° C. into a flask containing 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3,10-dione (5.54 mmol, 1.113 g). CH2Cl2 (30 mL) was added, and TiCl4 (2.77 mmol, 2.77 mL of 1 M solution in toluene) was gradually added and the mixture was warmed up to room temperature and stirred for 20 hours. Petroleum ether (20 mL) was added and then the mixture was filtered through CELITE. The filtrate was concentrated in vacuo to give 10-methylimino-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3-one as a red oil (1.28 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:22][CH3:23])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]3[CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:21]=1.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C.C(O)(C)C>[CH3:23][O:22][C:9]1[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[C:15](=[O:17])[O:16][C:11]=2[CH:10]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCCBr)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 37 %

Procedure:
Method B (20 h at 80° C.); starting materials: 8-(5-bromopentyloxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 85) and 4-phenylpiperidine; yield 37%; fusion point 103°-105° C. (from isopropanol and TBME). Fumarate: method E; yield 94%; fusion point 176°-178° C. (from isopropanol and TBME).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[NH:31][C:30](=[O:32])[CH:29]([C:33]([O:35][CH3:36])=[O:34])[CH:28]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:26]=2[CH:45]=1.IC>O1CCCC1.CCCCCC.CN(C)P(=O)(N(C)C)N(C)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]2[NH:31][C:30](=[O:32])[C:29]([C:33]([O:35][CH3:36])=[O:34])([CH3:1])[CH:28]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)[CH2:27][C:26]=2[CH:45]=1
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CI
Product: COC(=O)C1(C)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To 25 mmole (3 equiv.) of a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (prepared by addition of 9.6 ml of a 2.6 M solution of n-butyllithium in hexane to 7.5 ml of freshly distilled diisopropylamine in 50 ml of tetrahydrofuran at -78° C.) was added 3.0 g of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (8.35 mmole). After stirring at -78° C. for 1.5 hours, 1.5 ml of hexamethylphosphoric triamide was added along with 5.9 g of iodomethane (41.7 mmole, 5 equiv.). The reaction mixture was stirred at -78° C. to 20° C. for 6 hours, then quenched with 50 ml of 1N hydrochloric acid. The stirring was continued at 50° C. for 30 minutes. The layers were separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layer was washed with two 20 ml portions of saturated sodium bicarbonate, 20 ml of water then dried (magnesium sulfate) and concentrated. The residue was purified on a silica gel column. Elution with 25% ethyl acetate/hexanes gave 1.4 g of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-3-methyl-2H-1-benzazepin-2-one as a white solid.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1)CCC.[C:24]([O:32][CH2:33][C@:34]12[CH2:67][CH2:66][C@@H:65]([C:68]([CH3:70])=[CH2:69])[C@@H:35]1[C@@H:36]1[C@@:49]([CH3:52])([CH2:50][CH2:51]2)[C@@:48]2([CH3:53])[C@@H:39]([C@:40]3([CH3:64])[C@@H:45]([CH2:46][CH2:47]2)[C:44]([CH3:55])([CH3:54])[C:43](OS(C(F)(F)F)(=O)=O)=[CH:42][CH2:41]3)[CH2:38][CH2:37]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([O:32][CH2:33][C@:34]12[CH2:67][CH2:66][C@@H:65]([C:68]([CH3:70])=[CH2:69])[C@@H:35]1[C@@H:36]1[C@@:49]([CH3:52])([CH2:50][CH2:51]2)[C@@:48]2([CH3:53])[C@@H:39]([C@:40]3([CH3:64])[C@@H:45]([CH2:46][CH2:47]2)[C:44]([CH3:54])([CH3:55])[C:43]([C:6]2[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=2)=[CH:42][CH2:41]3)[CH2:38][CH2:37]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)no1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)OCC)no6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 85 °C
Yield: 20.3 %

Procedure:
To a sealable vial containing ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (0.052 g, 0.122 mmol) was added ((1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl benzoate (0.075 g, 0.111 mmol), lithium chloride (0.014 g, 0.332 mmol), and tetrakis(triphenylphosphine)palladium(0) (6.40 mg, 5.54 μmol). The mixture was diluted with 1,4-Dioxane (2 mL) and was flushed with N2. The vial was sealed and heated to 85° C. After 15.5 h of heating, the mixture was cooled to rt, was diluted with water (4 mL), and was extracted with dichloromethane (3×4 mL). The combined organic layers were dried over Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage flash chromatography using a 0-10% EtOAc in hexanes gradient. The fractions containing the expected product were combined and concentrated under reduced pressure. Ethyl 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)isoxazole-3-carboxylate was isolated as an off-white foam (0.015 g total mass, 0.022 mmol, 20.3% yield). LCMS: m/e 668.53 (M+H)+, 3.11 min (method 1).
Reaction SMILES: [CH3:1][O:2][NH:3][C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:19]3=[C:20]([CH:27]([CH3:29])[CH3:28])[C:21]([C:23]([NH:25][CH3:26])=[O:24])=[CH:22][N:18]3[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].[N:30]1([CH2:35]CN)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][NH:3][C:4]([C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:19]3=[C:20]([CH:27]([CH3:29])[CH3:28])[C:21]([C:23]([NH:25][CH2:26][CH2:35][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:24])=[CH:22][N:18]3[N:17]=[CH:16][N:15]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: CNC(=O)c1cn2ncnc(Nc3ccc(C)c(C(=O)NOC)c3)c2c1C(C)C
Reactant: NCCN1CCCC1
Product: CONC(=O)c1cc(Nc2ncnn3cc(C(=O)NCCN4CCCC4)c(C(C)C)c23)ccc1C

Procedure:
Example 19 was prepared from compound A of Example 18 and 2-pyrrolidin-1-yl-ethylamine by a method analogous to the preparation of Example 18 in similar yields LC/MS; (M+H)+=480.4.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[S:15][C:14]([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)=[CH:13][CH:12]=1.C(C1SC(Cl)=CC=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:60][C:61]1[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:62]=1[O:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1>CN(C=O)C.O>[F:60][C:61]1[CH:73]=[CH:72][C:71]([F:74])=[CH:70][C:62]=1[O:63][CH:64]1[CH2:65][CH2:66][N:67]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]2[CH:17]=[C:16]([C:14]3[S:15][C:11]([Cl:10])=[CH:12][CH:13]=3)[NH:20][N:19]=2)=[O:22])[CH2:68][CH2:69]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccc(Cl)s2)[nH]n1
Reactant: Fc1ccc(F)c(OC2CCNCC2)c1
Agent: CC(=O)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cc(F)ccc2F)CC1)c1cc(-c2ccc(Cl)s2)[nH]n1
Reaction time: 8 h
Yield: 62.4 %

Procedure:
DIPEA (120 mg, 0.98 mmol) was added to a stirred solution of {[5-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carbonyl]-amino}-acetic acid (80 mg, 0.28 mmol) (prepared by the method used for the synthesis of Intermediate 30, starting from 2-acetyl-5-chlorothiophene) in DMF (2 mL) followed by HOBt (40 mg, 0.29 mmol) and EDCI.HCl (56 mg, 0.29 mmol). After 5 minutes 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride (70 mg, 0.28 mmol) (prepared by method used for the synthesis of Intermediate 15) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from 10% EtOAc in hexane afforded 84 mg (65.1% Yield) of 5-(5-chloro-thiophen-2-yl)-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-difluoro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 481, 90.38%. 1H NMR (300 MHz, DMSO-d6): δ 13.6 (s, 1H), 8.6 (m, 1H), 7.18 (m, 4H), 7.1 (m, 1H), 6.8 (m, 1H), 4.7 (m, 1H), 4.2 (d, 2H), 3.8 (m, 1H), 3.7 (m, 1H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Yield: 57.6 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-bromo-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 36 (43 mg, yield 57.6%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7](=O)[CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Na].[C:43]1([SH:49])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>COC(C)(C)C.CN(C=O)C.C(#N)C>[CH2:1]([O:3][C:4]([N:6]=[C:7]([S:49][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:8]=[CH:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)NC(=O)C=CSc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: [Na]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)N=C(C=CSc1ccccc1)Sc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
N-ethoxycarbonyl-3-(phenylthio)acrylamide (1.20 g) was dissolved to acetonitrile (30 ml), then carbon tetrabromide (2.83 g) and triphenylphosphine (2.23 g) was added thereto and heat refluxing for three hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate20:1) to obtain light yellow oil. It was dissolved to DMF (10 ml), then sodium salt of thiophenol (0.63 g) was added thereto under ice cooling and stirred at room temperature for two hours. t-Butyl methyl ether (100 ml) was added to the reaction mixture, washed successively with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off inorganic salt and concentrated under reduced pressure. The residue was purified by medium pressure preparative high performance liquid chromatography to obtain phenyl N-ethoxycarbonyl-3-(phenylthio)thioacrylimidate (0.40 g) as light yellow oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH:8]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:10][CH:9]1[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH:8]1[CH2:12][C:11]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[O:10][CH:9]1[CH3:19])[CH3:6]
Reactant: CC1OC2(CCN(C)CC2)CC1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)NC1CC2(CCN(C)CC2)OC1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate was added to 3-Amino-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decane (1 g 5.4 mmol) in THF (20 ml). An additional 20 ml of THF were added and the reaction was stirred for 2 hours at room temperature. The THF solution was mixed with saturated sodium carbonate solution and the THF layer was separated, dried and evaporated to give a product which was purified by chromatography on silica gel and eluting with 5-10% ammoniated MeOH/CHCl3. The major fraction was converted to the fumaric acid salt in ether but a solid could not be obtained. The salt was neutralized with aqueous alkali and the base was extracted into methylene chloride. Concentration of the methylene chloride afforded the title carbamate compound as an oil.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[C:11]([CH:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:13][CH3:14])=[O:12].[CH:43]1([CH2:46]Br)[CH2:45][CH2:44]1>>[C:11]([CH:15]([N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[CH2:46][CH:43]1[CH2:45][CH2:44]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O:13][CH3:14])=[O:12]
Reactant: BrCC1CC1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(CC2CC2)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines with LiN(TMS)2 described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy -1-phenylmethyl)amino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine (Step A, Example 28) was alkylated with cyclopropylmethyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:24][NH:25][O:26][CH3:27].CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[C:3]([C:8]([N:25]([O:26][CH3:27])[CH3:24])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ncccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a suspension of 3-fluoropicolinic acid (17.7 g) in THF (300 mL) was added CDI (22.4 g) at room temperature, and the mixture was stirred at room temperature for 30 min and heated to 50° C. After stirring at 50° C. for 1 h, the mixture was cooled to room temperature. To the mixture were added N,O-dimethylhydroxylamine hydrochloride (18.4 g) and DIPEA (32.9 mL) at room temperature, and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt) to give the title compound (21.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[CH3:28][N:29](C)C=O>>[C:28]([C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])#[N:29]
Reactant: CN(C)C=O
Reactant: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(c2ccc([N+](=O)[O-])c(C#N)c2)OCCO1

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (9.8 g) and cuprous cyanide (4.0 g) in N,N-dimethylformamide (20 ml) was stirred and refluxed for 11 hours. An aqueous solution of sodium bicarbonate (200 ml) and ethyl acetate (100 ml) were added to the reaction mixture. The mixture was stirred and filtered. The filtrate was separated and the organic layer was dried and evaporated. The oily residue was purified by column chromatography on silica gel (200 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give yellow plates of 2-(3-cyano-4-nitrophenyl)-2-methyl-1,3-dioxolane (4.6 g).