Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.Cl[C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[NH2:22][C:11]1[N:12]=[CH:13][C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:24](=[O:31])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:20][CH:21]=2)=[N:15][C:10]=1[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCC(=O)N1CC=C(c2cnc(N)c(-c3nc4ccccc4[nH]3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(1H-benzimidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (50 mg, 0.12 mmol) in DCM (2 mL) at 0° C. was added methyl 4-chloro-4-oxo-butanoate (19 mg, 15 μL, 0.12 mmol) followed by the addition of triethylamine (50 mg, 69 μL, 0.5 mmol). The reaction mixture was stirred at room temperature for 2 h and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The crude material was dissolved in DMSO and purified by reverse phase HPLC using 1-99% MeOH in H2O to obtain methyl 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoate, which was re-dissolved in THF (1.0 mL), treated with NaOH (996 μL of 2.5 M, 2.5 mmol) and stirred for 18 h at room temperature. The reaction mixture was then acidified with conc. HCl till pH7 and extracted with DCM. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified via reverse phase HPLC using 1-99% MeOH in H2O (0.05% HCl modifier) to obtain 4-(4-(5-amino-6-(1H-benzo[d]imidazol-2-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-4-oxobutanoic acid (5 mg, 11%). 1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.66 (d, J=4.1 Hz, 2H), 7.27 (dd, J=6.0, 3.1 Hz, 2H), 6.68 (d, J=7.9 Hz, 1H), 4.34 (s, 1H), 4.27 (s, 1H), 3.84 (t, J=5.6 Hz, 2H), 2.85 (s, 1H), 2.80-2.65 (m, 3H), 2.56-2.47 (m, 2H). LC/MS m/z 393.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])=[O:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]=[C:27]=[S:28])[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][S:8]([NH:11][C:27]([NH:26][C:20]1[N:19]=[C:18]([O:17][CH3:16])[CH:23]=[C:22]([O:24][CH3:25])[N:21]=1)=[S:28])(=[O:10])=[O:9])=[O:4]
Reactant: COC(=O)c1ccccc1CS(N)(=O)=O
Reactant: COc1cc(OC)nc(N=C=S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1CS(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Temperature: 55 °C
Reaction time: 8.5 h
Yield: 771.9 %

Procedure:
A mixture of 2.5 g of (2-methoxycarbonylbenzyl)sulfonamide, 21.5 g of 4,6-dimethoxy-2-isothiocyanatopyrimidine and 15.1 g of anhydrous potassium carbonate in 400 ml of acetone is stirred for 8.5 hours at 55° C., and then filtered to collect precipitated crystals. To the filtrate, further 2 g of anhydrous potassium carbonate is added and stirred for 2 hours at 60° C. The precipitated crystals are collected. The combined crystals are suspended in 1.5 of water and adjusted to pH 2 with hydrochloric acid. After stirring the mixture for an hour, the crystals are collected by filtration, washed with water, dried and recrystallized from acetonitrile to give 35.9 g of the title compound, as white powder.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:28])[S:20][N:19]=2)=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.CN(C)C=O>O1CCCC1>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:22]([C:23]([NH2:25])=[O:24])=[C:21]([NH:26][C:27]([NH:29][CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:28])[S:20][N:19]=3)=[CH:14][CH:13]=2)=[O:9])=[CH:3][CH:2]=1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCCC1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nsc(NC(=O)NCCCN4CCCC4)c3C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Para-Tolyl isocyanate (4.5 g 0.0339 mol) was added to a solution of 3-(4-aminophenyl)-5-({[(3-pyrrolidin-1-ylpropyl)amino]carbonyl}amino)isothiazole-4-carboxamide (12.0 g, 0.0308 mol), diisopropylethylamine (6.0 g, 0.046 mol) in mixture of tetrahydrofuran (300 mL) and dimethylformamide (50 ml) at ambient temperature over 20 min. The resulting mixture was stirred at ambient temperature for 2 hr. The reaction mixture was concentrated in vacuo to give off white solid, which was stirred in 20% tetrahydrofuran and ethyl acetate (200 mL) mixture, filtered the solid and washed with ethyl acetate the title compound as a white solid (15.8 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([N:18]([C:21]1[N:26]=[N:25][C:24]([C:27]([O:29]CCCC)=[O:28])=[CH:23][CH:22]=1)[CH2:19][CH3:20])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([N:18]([C:21]1[N:26]=[N:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=1)[CH2:19][CH3:20])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)c1ccc(N(CC)C(C)c2cc(Br)ccc2OCc2ccccc2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(c1ccc(C(=O)O)nn1)C(C)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
n-Butyl 6-[N-(1-(2-benzyloxy-5-bromophenyl)-eth-1-yl)-N-ethylamino]pyridazine-3-carboxylate (180mg) was dissolved in THF (5 mL) and methanol (5 mL) and sodium hydroxide solution added (0.61 mL, 2M). The mixture was stirred for one hour at ambient temperature, and then the solvents evaporated off. The resulting foam was dissolved in water (20 mL) and pH adjusted to pH 4-5 with glacial acetic acid. A white precipitate formed which was filtered off, washed with water and dried for 17 hours at 5° C. to give 6-[N-(1-(2-benzyloxy-5-bromophenyl)eth-1-yl)-N-ethylamino]pyridazine-3-carboxylic acid (134 mg, mp 129.2° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([O:28]C(C)(C)C)=[O:27])[C:21]=4[CH3:33])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:34]=1.FC1C=C2C(=CC=1)NCC2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=[O:27])[C:21]=4[CH3:33])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:34]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)OC(C)(C)C)c3C)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Fc1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)c3C)CC1)C(=O)N2

Procedure:
70 mg (0.17 mmol) tert. butyl 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidin-4-carboxylate, 26 mg (0.19 mmol) 5-fluoroindoline, 61 mg (0.19 mmol) TBTU and 27 μL (0.19 mmol) TEA were stirred in 1.0 mL DMF for 3 h at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:19]([O:11][C:8]([CH:2]1[CH2:3][CH:4]2[O:7][CH:1]1[CH2:6][CH2:5]2)([CH3:9])[CH3:10])(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(O)C1CC2CCC1O2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: C=CC(=O)OC(C)(C)C1CC2CCC1O2
Reaction time: 1 h
Yield: 82 %

Procedure:
In 80 ml of toluene were dissolved 12.5 g of 2-(7-oxanorbornan-2-yl)-2-propanol, 12.1 g of triethylamine, and 0.4 g of 4-(N,N-dimethylamino)pyridine. Then 9.1 g of acrylic chloride was added to the solution at 50° C., which was stirred at the temperature for one hour. Water, 50 ml, was added to the solution below 30° C., followed by ordinary post-treatment. Vacuum distillation yielded 13.8 g of 2-(7-oxanorbornan-2-yl)-2-propyl acrylate. The two-step yield was 82%.
Reaction SMILES: [CH:1](/O)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br-].[Na+].[C:13](=[O:16])(O)[O-:14].[Na+]>ClCCl.O.[O-]Cl.[Na+]>[CH2:5]([C@H:6]1[CH2:7][C@H:8]1[CH2:9][C:13]([OH:14])=[O:16])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCC/C=C\O
Reactant: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: CCCCC[C@H]1C[C@H]1CC(=O)O

Procedure:
Cis-nonen-1-ol (10.0 g) is subjected to the cyclopropanation conditions as described in the preparation of Example 52. The resulting residue is taken up in 100 mL of dichloromethane at 0° C., followed by the addition of 800 mg of sodium bromide in 2 mL of water and 150 mg of 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical. To this mixture is added 1.50 g of Aliquot 336 followed by the dropwise addition of 9.2 g of sodium bicarbonate in 230 mL of 5% NaOCl. The aqueous phase is made basic, separated from the organic phase and acidified with concentrated HCl, and then extracted three times with dichloromethane. The combined organic layers are washed with water, dried over MgSO4, and concentrated in vacuo to give cis-2-(2'-pentylcyclopropyl)acetic acid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[C:12]2[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][NH:18][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH2:5][CH2:4][NH:3][C:28](=[O:30])[CH3:29])[CH:8]=[CH:9][CH:10]=2)[N:15]=[C:14]([CH3:17])[CH:13]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OCCN)c2n1
Agent: Cl
Product: CC(=O)NCCOc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 21. Starting materials were [8-(2-aminoethoxy)-2-methylquinolin-4-yl]-(3,4-dichlorobenzyl)-amine dihydrochloride and acetylchloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24]CC)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:22]([C:11]1[N:12]=[N:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:24]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
A mixture of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1.0 g) and 2-dimethylaminoethylamine (0.75 g) was heated for 30 minutes at 90° C. with stirring. After allowing to cool at ambient temperature, the resulting precipitates were collected by filtration, recrystallized from diethyl ether to give 3-(2-dimethylaminoethylcarbamoyl)-(3-nitrophenyl)-6-phenylpyridazine (1.04 g).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[NH:25][C:24]([C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[C:31]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[O:32])=[N:23][CH:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.Br[C:43]1[CH:44]=[CH:45][C:46]2[N:50]=[C:49]([C@@H:51]3[CH2:55][CH2:54][CH2:53][N:52]3[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:48][C:47]=2[CH:63]=1.C(=O)([O-])[O-].[K+].[K+]>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(COC)OC>[C:59]([O:58][C:56]([N:52]1[CH2:53][CH2:54][CH2:55][C@H:51]1[C:49]1[NH:48][C:47]2[CH:63]=[C:43]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[NH:25][C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31]([O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)=[O:32])=[N:23][CH:22]=5)=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[CH:44]=[CH:45][C:46]=2[N:50]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC1(C)OB(c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)cc3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)cc4)cc3)cc2[nH]1
Temperature: 85 °C
Yield: 44.5 %

Procedure:
A mixture of (S)-benzyl 2-(5-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.1 g, 3.8 mmol), (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.6 g, 4.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.44 mg, 0.38 mmol), 2M aqueous potassium carbonate solution (7.7 mL, 15.4 mmol) and dimethoxyethane (26 mL) was degassed under a stream of argon for 15 minutes. The reaction was heated to 85° C. for 14 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.2 g, 44%). LCMS-ESI+: calculated for C43H44N6O4: 708.85; observed [M+1]+: 709.41.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:18])=[C:11]([CH3:17])[C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.Cl.[N:20](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[OH:21].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:17][C:11]1[C:12](=[O:16])[O:13][C:14]2[C:9]([C:10]=1[CH3:18])=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][C:22](=[N:20][OH:21])[CH2:23][CH2:24]1)[CH:15]=2
Reactant: ON=C1CCNCC1
Reactant: Cc1c(C)c2ccc(OCCCBr)cc2oc1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(C)c2ccc(OCCCN3CCC(=NO)CC3)cc2oc1=O

Procedure:
By the reaction of 7-(3-bromopropoxy)-3,4-dimethylcoumarin with 4-oximino-piperidine hydrochloride in dioxane solution in the presence of a Hunig base, there is obtained 3,4-dimethyl-7-[3-(4-oximino-piperidino)-propoxy]-coumarin (m.p. 198°-200° C.), from which, by catalytic hydrogenation over Raney nickel in ammoniacal methanol, there is obtained 7-[3-(4-amino-piperidino)-propoxy]-3,4-dimethyl-coumarin; m.p. 92°-94° C.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.CCCCCC.[C:22](#[N:26])[CH:23]([CH3:25])[CH3:24].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:24][C:23]([CH3:25])([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]#[N:26]
Reactant: ClCc1ccccc1
Reactant: CC(C)C#N
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C#N)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
A solution of N-isopropylcyclohexyl amine (2.8 g, 19.72 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. was treated with 1.6 M n-butyl lithium in hexane (12.23 mL, 19.72 mmol) drop-wise over 15 minutes. The reaction solution was stirred for 10 min at −78° C. The solution turned yellow from colorless. Isobutyronitrile (1.36 g, 19.72 mmol) was added to the reaction solution, and the reaction mixture was stirred for a further 10 min at −78° C. This solution was syringed into a solution of benzyl chloride (2.62 g, 20.71 mmol) in anhydrous tetrahydrofuran at −78° C. under a nitrogen atmosphere. The reddish/brown reaction was solution stirred for 1 h at −78° C. The dry ice/acetone bath was then removed, and the solution stirred at room temperature for 5 h. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL). Ethyl acetate (25 mL) was added to the quenched reaction solution. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to yield 3.18 g of crude material. The crude material was partitioned between 2 N hydrochloric acid solution and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give 2.18 g (69%) 2,2-dimethyl-3-phenylpropanenitrile. 1H NMR (DMSO-d6, 400 MHz) δ 7.369-7.333 (m, 2H), 7.309-7.270 (m, 3H), 2.832 (s, 2H), 1.294 (s, 6H). This compound was used in subsequent reaction with out further analysis.
Reaction SMILES: C([N:4]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:20])[CH:18]=2)[C:6]2([CH2:11][CH2:10][S:9](=[O:13])(=[O:12])[CH2:8][CH2:7]2)[CH2:5]1)(=O)C.Cl>CO>[Br:20][C:17]1[CH:18]=[C:19]2[NH:4][CH2:5][C:6]3([CH2:11][CH2:10][S:9](=[O:13])(=[O:12])[CH2:8][CH2:7]3)[C:14]2=[CH:15][CH:16]=1
Reactant: CC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(Br)cc21
Agent: Cl
Solvent: CO
Product: O=S1(=O)CCC2(CC1)CNc1cc(Br)ccc12

Procedure:
A mixture of 1-acetyl-6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide (0.75 g, 2.1 mmol) and 5 N HCl (8 mL) in MeOH (20 mL) was heated at reflux for 3 h. After this time the solvent was removed in vacuo to give 6-bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide as an off-white solid. Purification by column chromatography gave 6-Bromo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide. Mass Spectrum (ESI) m/e=316.0 [(M+1) (79Br)] and 318.0 [(M+1) (81Br)]
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])(O)=[O:2].[OH-].[NH4+:23]>>[NH2:23][C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])=[O:2]
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(N)=O

Procedure:
Three g of the product of Example 65 was reacted with 0.7 g of 35% ammonium hydroxide, substantially as shown in Example 60, to obtain 2 g of the desired product, m.p. 178°-180°.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]1[C:48](=[O:49])[NH:47][C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[CH2:44][CH2:43]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:10])[NH:41][C@@H:42]1[C:48](=[O:49])[NH:47][C:46]2[CH:50]=[CH:51][CH:52]=[CH:53][C:45]=2[CH2:44][CH2:43]1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCc2ccccc2NC1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCc4ccccc4NC3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (5.0 mg, 0.0088 mmol) and (S)-3-amino-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (1.6 mg, 0.0088 mmol) to give a white solid (5.1 mg, 80% yield). Anal. Calcd. for C41H48N4O6S m/z 724.9. found: 725.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.24-6.90 (m, 14H), 6.28-6.20 (m, 1H), 5.29-5.20 (m, 1H), 5.04-4.97 (m, 2H), 4.93-4.84 (m, 2H), 4.30-4.20 (m, 1H), 3.60-3.53 (m, 3H), 3.20-3.04 (m, 1H), 2.82-2.50 (m, 8H), 2.37-2.19 (m, 4H), 1.96-1.88 (m, 2H), 1.85-1.68 (m, 2H), 1.67-1.31 (m, 6H), 1.27-1.14 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:5]4[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=4)[CH:8]=3)[CH2:30][CH2:29]2)[CH:23]=1)=[O:20]
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: Cc1ccc(Oc2cccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2)cc1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-methylphenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 443.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[N:8]=[C:9](/[O:16][CH2:17][CH3:18])\[CH2:10][C:11]([O:13]CC)=O)=[CH:4][C:3]=1[O:19][CH3:20]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:19][CH3:20])[N:8]=[C:9]([O:16][CH2:17][CH3:18])[CH:10]=[C:11]2[OH:13]
Reactant: CCOC(=O)C/C(=N\c1ccc(Br)c(OC)c1)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOc1cc(O)c2cc(Br)c(OC)cc2n1
Temperature: 250 °C
Reaction time: 0.08 h

Procedure:
A solution of ethyl (3E)-3-[(4-bromo-3-methoxyphenyl)imino]-3-ethoxypropanoate (30.0 g, 87 mmol) in DOWTHERM (30 mL) was added to a stirred solution of DOWTHERM (300 mL) at 250° C. The resulting solution was stirred at 250° C. for 5 minutes, cooled to RT and filtered, and the cake was washed with hexane (3×50 mL), then dried to give the title product. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H); 6.92 (s, 1H); 5.80 (s, 1H); 4.27 (q, J=7.1 Hz, 2H); 3.97 (s, 3H); 1.46 (t, J=7.0 Hz, 3H) ppm. LRMS (ESI) m/z 298.0 [(M+H)+; calcd for C12H13BrNO3: 298.0].