Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=CC(C(N2CCN(C3C(C)=CC(C)=CN=3)CC2)=O)=C(F)C=1.COC1C=CC(CN2C(=O)C(C)(C)NC2=O)=CC=1.[CH3:43][C:44]1[C:45]([N:51]2[CH2:56][CH2:55][N:54]([C:57]([C:59]3[CH:64]=[CH:63][C:62]([N:65]4[C:69]([CH3:71])([CH3:70])[C:68](=[O:72])[N:67](CC5C=CC(OC)=CC=5)[C:66]4=[O:82])=[CH:61][C:60]=3[F:83])=[O:58])[CH2:53][CH2:52]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1>>[CH3:43][C:44]1[C:45]([N:51]2[CH2:52][CH2:53][N:54]([C:57]([C:59]3[CH:64]=[CH:63][C:62]([N:65]4[C:69]([CH3:71])([CH3:70])[C:68](=[O:72])[NH:67][C:66]4=[O:82])=[CH:61][C:60]=3[F:83])=[O:58])[CH2:55][CH2:56]2)=[N:46][CH:47]=[C:48]([CH3:50])[CH:49]=1
Reactant: COc1ccc(CN2C(=O)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(F)c3)C(C)(C)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)(C)C2=O)cc1
Agent: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4(C)C)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (235 mg) described in Preparation Example 114 and 3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (149 mg) described in Preparation Example 53 and by the reaction and treatment in the same manner as in Example 508, the title compound (130 mg) was obtained via 1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-3-(4-methoxybenzyl)-5,5-dimethylimidazolidine-2,4-dione.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[CH:28]=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:31][OH:32]>CO>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:21][CH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][CH2:25]2)[C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C@H:9]1/[CH:28]=[N:31]/[OH:32])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](C=O)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Product: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](/C=N/O)N(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of (2S,4S)-1-Boc-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2-formylpyrrolidine (312 mg, 0.88 mmol) prepared in Step A in methanol (5 ml) and TEA (0.64 ml, 4.4 mmol) was added hydroxylamine hydrochloride (305 mg, 4.4 mmol), and stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (208 mg, 67%).
Reaction SMILES: C(O[C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[Cl:27])[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=O)[C@@H:18]4[CH2:28][C@@H:19]42)[CH:14]=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=O)[CH3:7])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Cl:27][C@@H:24]1[C@@:25]2([CH3:26])[C@@H:11]([CH2:10][CH:9]=[C:5]2[CH2:6][CH3:7])[C@H:12]2[C@@H:22]([C@:20]3([CH3:21])[C:15]([CH:14]=[CH:13]2)=[CH:16][CH2:17][C@@H:18]2[CH2:28][C@H:19]32)[CH2:23]1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3C[C@H](Cl)[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCC1=CC[C@H]2[C@@H]3C=CC4=CC[C@@H]5C[C@@H]5[C@]4(C)[C@H]3C[C@H](Cl)[C@]12C
Yield: 63.4 %

Procedure:
One gram of 17α-acetoxy-12α-chloro-1α,2α-methylene-4,6-pregnadiene-3,20-dione is treated analogously to Example 1 in "Dowtherm" for 1 hour at 280° C. and worked up. Recrystallization from isopropyl ether yields 500 mg of 12α-chloro-1α,2α-methylene-4,6,16-pregnatriene (61% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[Br:14][C:15]1[N:20]=[C:19]([CH:21]=[O:22])[CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:21]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:14])[N:20]=2)[OH:22])[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: Brc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cccc(Br)n1)c1cccc(Br)n1
Reaction time: 0.33 h

Procedure:
To the solution of 2,6-dibromopyridine (4.72 g, 19.93 mmol) in THF (100 mL) at −78° C. was added n-BuLi (8.8 mL, 2.5 M, 22 mmol) and stirred for 20 min. 6-Bromo-2-pyridinecarboxaldehyde (3.71 g, 19.93 mmol) was added. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (15% EtOAc in hexane) to give bis(6-bromopyridin-2-yl)methanol. LRMS m/z (M+H) Calcd: 345.0, found: 344.9.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:18][CH2:19][CH:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>CC#N>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][CH:20]([OH:32])[CH2:19][NH:18][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:10]=1
Reactant: O=C(O)c1cccc(C(=O)N2CCOCC2)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(C(=O)N2CCOCC2)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 7.5 %

Procedure:
To a solution of 3-(morpholine-4-carbonyl)benzoic acid (300 mg crude, 0.48 mmol) in MeCN (5 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)-propan-2-ol (100 mg, 0.49 mmol), and TEA (250 mg, 2.48 mmol) and the resulting mixture was stirred at 20° C. for 10 min. BOPCl (120 mg, 0.49 mmol) was added and the reaction mixture was stirred at 20° C. for 1 h. After evaporation of the solvent, the residue was purified by prep-HPLC to give the title compound (15.2 mg, Yield 7.5%). 1H NMR (CD3OD, 400 MHz): δ 7.85-7.94 (m, 2H), 7.60 (d, J=7.8 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.08-7.16 (m, 3H), 7.01-7.07 (m, 1H), 4.14 (quin, J=6.0 Hz, 1H), 3.76 (s, 6H), 3.54-3.68 (m, 3H), 3.47 (dd, J=6.8, 13.6 Hz, 3H), 2.80-2.98 (m, 4H), 2.63-2.74 (m, 2H). LCMS (m/z): 424.2 (M+1).
Reaction SMILES: C(N1C2C(=CC=C(N)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C.[C:22]([N:25]1[C:34]2[C:29](=[CH:30][C:31](C3C=NN(C4CC4)C=3)=[C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=2)[N:28]([C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49])[CH2:27][C@@H:26]1[CH3:54])(=[O:24])[CH3:23]>>[C:22]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[CH:33]=2)[N:28]([C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49])[CH2:27][C@@H:26]1[CH3:54])(=[O:24])[CH3:23]
Reactant: CC(=O)N1c2cc(NS(C)(=O)=O)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: CC(=O)N1c2cc(N)ccc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2cc(NS(C)(=O)=O)ccc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-3-methyl-6-(methylsulfonamido)-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-6-(methylsulfonamido)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 234). MS (ESI, pos. ion) m/z 392 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH2:15]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:7])[CH2:3][C:4](=[O:5])[NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8]1
Reactant: NC1CCCCC1N
Reactant: CC(C)=CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)N[C@@H]2CCCC[C@H]2N1
Yield: 10.2 %

Procedure:
10.8 g β,β-dimethylacrylic acid was placed in a 250 ml flask, and 10 ml toluene was added followed by 11.4 g 1,2-diaminocyclohexane. The mixture is heated under an inert gas atmosphere, preferably argon, at 175°-180° C. with a Dean-Stark trap. 1.6 ml water was collected. The mixture is cooled down after 7 hr. Toluene was removed under vacuum. The reaction product obtained is recrystallized from acetone to give 2 g of a white crystalline product having a m.pt. of 188°-189° C.
Reaction SMILES: C[Al](C)C.[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[N:23][O:24][C:25]=2[CH2:26][OH:27])=[N:15][CH:14]=1>O1CCOCC1>[CH:7]1([CH2:6][NH:5][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=4)=[N:23][O:24][C:25]=3[CH2:26][OH:27])=[N:15][CH:14]=2)[CH2:9][CH2:8]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
Trimethylaluminium solution (2 M in toluene, 0.8 mL, 1.60 mmol) was added to a solution of aminomethylcyclopropane (78 mg, 1.06 mmol) in dioxane (5 mL). The mixture was stirred for 1 h at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:3 to 3:2) to afford the title compound (30 mg, 27%) as a colourless oil. MS: m/e=416.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[C:48]([N:51]3[C:56](=[O:57])[CH2:55][C:54]([CH3:59])([CH3:58])[CH2:53][C:52]3=[O:60])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[C:48]([N:51]3[C:52](=[O:60])[CH2:53][C:54]([CH3:59])([CH3:58])[CH2:55][C:56]3=[O:57])[CH:49]=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CCCCc1nc2ccc(N3C(=O)CC(C)(C)CC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 400 mg (0.5 mMol) of 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)-benzimidazol-1-yl]-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl in 10 ml of methanol is mixed with 1.5 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with 15 ml of water and made alkaline with concentrated ammonia, whereupon the product goes into solution. By acidification with glacial acetic acid, the crude product is precipitated and then purified by column chromatography (150 g of silica gel; eluant: methylene chloride +5% ethanol).
Reaction SMILES: COC(C(S(C)(=O)=O)(CCCC(OC(=O)C)CCCCC)CCCCCCC(OC)=O)=O.COC([C:37]([S:63]([CH3:66])(=[O:65])=[O:64])([CH2:48][C:49]#[C:50][CH:51]([O:59][C:60](=[O:62])[CH3:61])[C:52]([CH3:58])([CH3:57])[CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])=O>>[CH3:66][S:63]([CH:37]([CH2:48][C:49]#[C:50][CH:51]([O:59][C:60](=[O:62])[CH3:61])[C:52]([CH3:57])([CH3:58])[CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])(=[O:64])=[O:65]
Reactant: CCCCC(C)(C)C(C#CCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Product: CCCCC(C)(C)C(C#CCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out by the procedure of Example 3, Step D, except that methyl 8-methoxycarbonyl-8-methylsulfonyl-12-acetoxyheptadecanoate is replaced by an equivalent quantity of methyl 8-methyoxycarbonyl-8-methylsulfonyl-12-acetoxy-13,13-dimethyl-10-heptadecynoate.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C:5](=[CH:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.O.[OH-].[Na+].Cl>[Pd].C(OCCCC)(=O)C>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([CH2:29][CH3:30])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: CC=C1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCOC(C)=O
Product: CC[C@H]1C(=O)[C@@H]2[C@H](CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]23)[C@@]2(C)CC[C@@H](O)C[C@@H]12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of purified compound 5 (110 g, 264 mmol), water (1100 mL), caustic soda solution (35.8 mL, 682 mmol) at 50% and palladium catalyst (Pd/C, 11 g) were charged to a hydrogenation reactor. The temperature was adjusted to 25° C. to 35° C. and the reactor was flushed three times with nitrogen (2 bar) and three times with hydrogen (1 bar). These pressure values were given relative to ambient pressure (=0 bar). A hydrogen pressure of 5 bar was applied and the reaction mixture was heated up to 100° C. (for isomerisation to the alpha position) over a period of 1.5 hours and then stirred for 3 hours while maintaining the hydrogen pressure at 4.5 to 5 bar. The reaction mixture is then cooled to 40° C. to 50° C. For the workup, the Pd/C is filtered off. To the filtrate, n-butyl acetate (1320 mL) and hydrochloric acid (67.8 mL, 815 mmol, 37%) were added. The aqueous phase was separated and discarded. The organic phase was treated with activated carbon (5.5 g) for about 10 minutes at 40 to 50° C. The activated carbon was filtered off and the filtrate was condensed by distillation and the resulting suspension was cooled to 15° C. to 20° C. within 2 to 3 hours. The precipitated compound 6 was isolated and washed with n-butyl acetate (160 mL). The product was filtered using a pressure filter. Drying was done in the pressure filter under vacuum at approximately 60° C. This leads to 89.8 g (81.2%) of Compound 6. Compound 5A, a mixture of E/Z isomers, can be used in step 5 to prepare Compound 6.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[C:8]1([CH:14]([O:21][C:22](=[O:54])/[C:23](/[N:27]2[CH:30]([S:31][S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:29]([NH:42][C:43](=[O:52])[CH2:44][O:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:28]2=[O:53])=[C:24](\[OH:26])/[CH3:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[Cl-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl.O.C(OCC)(=O)C>[C:8]1([CH:14]([O:21][C:22](=[O:54])/[C:23](/[N:27]2[CH:30]([S:31][S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:33])=[O:34])[CH:29]([NH:42][C:43](=[O:52])[CH2:44][O:45][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:28]2=[O:53])=[C:24](/[O:26][CH3:1])\[CH3:25])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: COS(=O)(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CO/C(C)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
(avii) 1.08 g (3 mmols) of tetrabutylammonium iodide and 1.9 ml (2.52 g, 20 mmols) of dimethylsulphate are added to a suspension of 3.36 g (5 mmols) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) in 15 ml of carbon tetrachloride and 10 ml of water. The mixture is vigorously stirred at room temperature and 1 N sodium hydroxide solution is added to it by means of an automatic titrator in sufficient amount to keep the pH constant at 7.0. In the course of 4-5 hours, 1.5-2 equivalents of sodium hydroxide solution are consumed. The mixture is diluted with ethyl acetate and water and a little sodium chloride is added. The organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is crystallised from a little ethyl acetate/hexane, 1:1, and gives 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-iso-crotonic acid diphenylmethyl ester.
Reaction SMILES: [C:1]([C:3]1[C:4]([S:18][CH2:19][CH3:20])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:21][NH:22][CH3:23]>>[CH3:21][N:22]([CH3:23])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([S:18][CH2:19][CH3:20])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CCSc1nsc(NC(=O)Oc2ccccc2)c1C#N
Reactant: CNC
Product: CCSc1nsc(NC(=O)N(C)C)c1C#N
Yield: 160 %

Procedure:
Two samples (30.9 g each) of phenyl (4-cyano-3-(ethylthio)-5-isothiazolyl)carbamate were reacted with dimethylamine (9.13 g per batch) in the manner described in Example IV B. The reaction mixtures from the two runs were combined and processed as in IV B to give 41.5 g of 1,1-dimethyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea, m.p. 198° after recrystallization from ethanol. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl.[C:2]1([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[K+]>O.C(O)C>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:19])[NH2:17]
Reactant: [N-]=C=O
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NC(=O)N1CC(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture comprising 2.3 g of 3-phenyl indoline hydrochloride in 23 ml of water and 0.81 g of potassium isocyanate in 23 ml of ethanol was stirred for 15 minutes at room temperature. The precipitate which resulted was filtered off, washed with water and recrystallized from dilute ethanol. The yield of N-carbamoyl-3-phenylindoline was 0.9 g and the product had a melting point of 144°-145° C.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[CH2:10]([NH:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH:32]([CH3:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:25]([CH3:41])([CH3:40])[CH2:24]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH3:8][C:5]1([CH3:9])[CH2:6][O:7][P:2]([N:22]([CH:23]2[CH2:28][C:27]([CH3:29])([CH3:30])[N:26]([O:31][CH:32]([CH3:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:25]([CH3:40])([CH3:41])[CH2:24]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:3][CH2:4]1
Reactant: CCCCCCCCCCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1
Reactant: CC1(C)COP(Cl)OC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(C1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1)P1OCC(C)(C)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of 3.03 grams (18.0 mmol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane in 10 ml of tetrahydrofuran is added over ten minutes to a solution of 8.00 grams (18.0 mmol ) of 4-dodecylamino-1-alpha-methylbenzyloxy2,2,6,6-tetramethylpiperidine, 1.91 grams (18.9 mmol) of triethylamine, and 25 ml of tetrahydrofuran. The reaction temperature increases from 20° C. to 30° C. during the addition, and triethylamine hydrochloride precipitates from solution. The reaction mixture is stirred at ambient temperature for two hours. The precipitate is removed by filtration, and the filtrate is concentrated at reduced pressure. Residual volatiles are removed by Kugelrohr distillation (at 100° C./0.2 mm) to afford 10.1 grams (97% yield) of the title compound as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH2:23]([N:26]1[CH:30]=[C:29]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:28]=[C:27]1[C:37]#[N:38])[CH:24]=[CH2:25]>C1COCC1>[CH2:23]([N:26]1[CH:30]=[C:29]([C:31]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:36])[C:32]([F:35])([F:33])[F:34])[CH:28]=[C:27]1[C:37]#[N:38])[CH:24]=[CH2:25]
Reactant: C=CCn1cc(C(=O)C(F)(F)F)cc1C#N
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (1.3 g, 4.3 mmol, 1.1 equiv.) in 20 mL of THF was added n-BuLi (2.5 M in hexanes, 1.7 ml, 4.3 mmol, 1.1 equiv.) followed by a chilled (−78° C.) solution of 1-allyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrole-2-carbonitrile (0.9 g, 3.9 mmol, 1 equiv.) in 3 mL of THF. After 30 minutes, the mixture was warmed to 0° C., quenched with water, diluted with brine, and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (5-30% gradient) to afford 1.15 g (66%) of the title compound as an off-white solid. MS m/z 441.26 (MH+).
Reaction SMILES: C([NH:11][CH2:12][C:13]([NH:15][C:16]([C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH:27]1[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:25])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(OCC1C=CC=CC=1)=O.Br>C(O)(=O)C>[NH2:11][CH2:12][C:13]([NH:15][C:16]([C:24]([N:26]1[CH2:31][CH2:30][NH:29][C:28](=[O:32])[CH:27]1[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:25])=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14]
Reactant: CC(C)CC1C(=O)NCCN1C(=O)C(=Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)CC1C(=O)NCCN1C(=O)C(=Cc1ccccc1)NC(=O)CN

Procedure:
4-[N-carbobenzyloxyglycyldehydrophenylalanyl]-3-(2-methylpropyl)piperazinone (XXXVI, Example 69, 0.5 g.) is added to a solution of hydrogen bromide (32%) in acetic acid (5 ml.). After 1 hour the diluents are evaporated to give the title compound as the hydrobromide salt.
Reaction SMILES: [CH3:1]C1CCCC2(C(=O)CCC2)C1.[CH3:13][CH:14]1[CH2:24][CH2:23][C:17]2([C:21](=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:16][CH2:15]1.C[Li]>>[CH3:1][C:21]1([OH:22])[C:17]2([CH2:23][CH2:24][CH:14]([CH3:13])[CH2:15][CH2:16]2)[CH2:18][CH2:19][CH2:20]1
Reactant: CC1CCC2(CCCC2=O)CC1
Reactant: CC1CCCC2(CCCC2=O)C1
Agent: [Li]C
Product: CC1CCC2(CCCC2(C)O)CC1
Yield: 43 %

Procedure:
A mixture of 7-methylspiro[4,5]decan-1-one and 8-methylspiro[4,5]decan-1-one and methyl lithium were reacted together according to the general procedure (example 2, procedure 5) to give the title compound in 43% yield. The crude product was purified by column chromatography on silicagel (eluent: cyclohexane/ethyl acetate 29:1) and bulb-to-bulb distillation (B.p.=68° C./0.04 mbar).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=5[N:8]([CH3:11])[C:9]=4[CH:10]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 30.7 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (300 mg, 0.792 mmol) and 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (187 mg, 0.792 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 30%) as a yellow oil: ESI MS m/z 535 [M+H]+.