Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CN1CCN(C)C1=O>C1COCC1>[CH2:8]([C:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: c1cc[cH-]c1
Reactant: CCCCCCCCBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Product: CCCCCCCCC1=CC=CC1
Temperature: -78 °C

Procedure:
THF in a volume of 100 ml was added to 50 ml (100 mmol) of a 2 M THF solution of sodium cyclopentadienide, and the mixture was cooled to −78° C. A THF solution of 19.3 g (100 mmol) of 1-bromooctane was added thereto dropwise. Further, 11.4 g (100 mmol) of 1,3-dimethyl-2-imidazolidinone was added dropwise. The mixture was stirred at −78° C. The mixture was further stirred at room temperature for 24 hours and was cooled to 0° C. The reaction was terminated by adding 1N hydrochloric acid, and hexane was added to the reaction liquid. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, was filtered, and was concentrated under reduced pressure. The concentrate was purified by distillation under reduced pressure to give 6.7 g (37.5 mmol) of target n-octylcyclopentadiene. The compound was identified by GC-MS. GC-MS: 178 (MS).
Reaction SMILES: C([O:14][C:15]([C:17]1[O:18][C@@H:19]([C:45](=[O:53])[N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[C@H:20]([NH:41][C:42](=[O:44])[CH3:43])[C@@H:21]([NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)[CH:22]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>ClCCl>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[C:42]([NH:41][C@H:20]1[C@H:19]([C:45](=[O:53])[N:46]([CH2:50][CH2:51][CH3:52])[CH2:47][CH2:48][CH3:49])[O:18][C:17]([C:15]([OH:16])=[O:14])=[CH:22][C@@H:21]1[NH:23][C:24]([NH2:33])=[NH:25])(=[O:44])[CH3:43]
Reactant: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](NC(=N)N)[C@H]1NC(C)=O
Reaction time: 2 h

Procedure:
(4S,5R,6R)-5-Acetylamino-4-[2,3-bis(tert-butoxycarbonyl)-guanidino]-6-dipropylcarbamoyl-5,6-dihydro-4H-pyran-2-carboxylic acid benzhydryl ester (0.32 g) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and left to stand at 23° C. for 2 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether (20 ml). The resulting solid was collected by filtration and dried to give the title compound as an off-white solid. (0.158 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:29][N+:30]([O-:32])=O)[CH2:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:35](Br)=[CH2:36].C1(N=C=O)C=CC(N=C=O)=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]([C:29]3[CH:36]=[CH:35][O:32][N:30]=3)[CH2:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[O:18])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C=CBr
Reactant: COc1ccc(COC(=O)CC(C[N+](=O)[O-])c2ccc(OCc3ccc(OC)cc3)cc2)cc1
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)CC(c2ccc(OCc3ccc(OC)cc3)cc2)c2ccon2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Triethylamine (1 mL) was added to a mixture of 6.3 (1.89 g, 4.1 mmol), vinyl bromide (32.5 mL, 1.0 M solution in THF) and 1,4-phenylene diisocyanate (2.3 g, 14.35 mmol). The mixture was stirred at 80° C. for 8 hours. After cooling, the solid was removed from the mixture by filtration, and the filtrate was concentrated and purified by flash chromatography to give 6.4 (3 g). MS ESI (pos.) m/e: 474 (M+H). 1HNMR (CDCl3) δ 8.28 (d, 1H), 7.37 (d, 2H), 7.18 (m, 4H), 6.92 (m, 6H), 6.07 (d, 1H), 5.02 (s, 2H), 4.97 (s, 2H), 4.59 (t, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.33 (dd, 1H), 3.00 (dd, 1H).
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([F:14])=[CH:6][C:5]=1[CH2:15]Br.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[CH3:27])[CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:19]([F:18])[CH:20]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(F)cc1C(F)(F)F
Reactant: Cc1ccc(CN)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(CN2Cc3cc(F)cc(C(F)(F)F)c3C2=O)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A mixture of 4-fluoro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.100 g, 0.32 mmol), 3-fluoro-4-methyl-benzylamine (0.060 mL, 0.42 mmol), and K2CO3 (0.088 g, 0.64 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-2-(3-fluoro-4-methyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.034 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.25 (s, 3H), 4.28 (s, 2H), 4.74 (s, 2H) 6.98 (t, 2H), 7.16 (t, 1H), 7.27 (d, 1H), 7.51 (d, 1H). GC-MS: m/z 341 (M)+, 320 (M−21)+.
Reaction SMILES: C=C([CH2:6][CH2:7][C:8]1[C:13]([O:14][C:15](=O)[CH3:16])=[C:12]([CH3:18])[C:11]([CH3:19])=[C:10]([O:20]C(=O)C)[C:9]=1[CH3:24])CC#N.[OH-:25].[K+].[CH2:27]([OH:30])[CH2:28]O.Cl>O>[OH:20][C:10]1[C:11]([CH3:19])=[C:12]([CH3:18])[C:13]2[O:14][C:15]([CH2:28][C:27]([OH:30])=[O:25])([CH3:16])[CH2:6][CH2:7][C:8]=2[C:9]=1[CH3:24]
Reactant: C=C(CC#N)CCc1c(C)c(OC(C)=O)c(C)c(C)c1OC(C)=O
Reactant: [OH-]
Reactant: OCCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 623 mg (1.89 mmoles) of the mixture of E- and Z-3-methyl-5-(2,4,5-trimethyl-3,6-diacetyloxyphenyl)-3-pentenenitrile and 3-methylene-5-(2,4,5-trimethyl-3,6-diacetyloxy-phenyl)pentanenitrile, 498 mg (7.70 mmoles) of 85% KOH, 5 ml of ethylene glycol and 0.5 ml of water was stirred and refluxed for 36 hr. The reaction mixture was cooled to room temperature, then poured into water. The pH of the solution was adjusted to 8 with 1 N aqueous HCl and the resulting mixture was extracted with two portions of ether (the extracts were discarded). The aqueous phase was acidified with 3 N aqueous HCl and worked-up with ether in the usual manner giving 421 mg (84%) of rac.-(6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)acetic acid as a tan solid, mp 168°-170°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]1[CH2:23][O:22]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]>O1CCCC1>[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][CH:21]([OH:22])[CH2:23][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[N:15]=[CH:14][CH:13]=[C:12]2[O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])=[C:27]([F:42])[CH:26]=1)#[N:8]
Reactant: C1CCNCC1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC1CO1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1OCC(O)CN1CCCCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1.5 ml) and piperidine (0.08 ml) to N-[4-(6-cyano-7-oxiranylmethoxyquinolin-4-yloxy)-2-fluorophenyl]-N′-(4-fluorophenyl)urea (78 mg), the mixture was heated at 50° C. for 30 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (32 mg) as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=O)[CH:5]=[CH:6][CH:7]=1>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:10](=[O:12])[C:9]1[CH:14]=[CH:15][CH:16]=[N:17][C:8]2=1.[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10](=[O:12])[C:9]1[CH:14]=[CH:15][CH:16]=[N:17][C:8]2=1
Reactant: COC(=O)c1cccnc1-c1cccc(Br)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ccc(Br)cc2-c2ncccc21
Product: O=C1c2cccnc2-c2cccc(Br)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 500 mL r.b. flask containing 1 g of methyl 2-[3-bromophenyl]nicotinate and 30 g of polyphosphoric acid with a stirring bar was dipped in an oil bath at 210° C. While the contents were being warmed, house vacuum (~30 mmole) was slowly applied. After 15 mins., the reaction mixture started to stir easily and slowly started turning orange. This reaction mixture was stirred at 210° and 30 mm pressure for 4 hrs. The flask was taken out and while it was still warm, ~50 g of ice was cautiously added to the reaction mixture. After cooling the stirring reaction mixture to 0°, 60 mL of 5N sodium hydroxide was added slowly over 3 mins. The resulting green solid was filtered and washed thoroughly with 5×25 mL of water. This crude solid was taken up in methylene chloride and applied on silica gel and eluted with 1:20 ethyl acetate:hexane mixture to give a 1:2 ratio of 6-bromo-4-aza-9-fluorenone and 8-bromo-4-aza-9-fluorenone as yellow solids. ##STR18##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:34][CH2:35][CH2:36][NH:37][C:38]1[N:46]=[C:45]([Cl:47])[N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:34][CH2:35][CH2:36][NH:37][C:38]1[N:46]=[C:45]([Cl:47])[N:44]=[C:43]2[C:39]=1[N:40]=[CH:41][N:42]2[CH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:7]
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: O=C(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
190 mg of 3-chlorobenzoic acid, 205 mg of 1-hydroxybenzotriazole hydrate, 287 mg of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 4 ml of dichloromethane are mixed together, 280 mg of the product obtained in Stage 1 of Example 7 is added and the reaction medium is agitated for 5 hours and 30 minutes at ambient temperature. Water is added, followed by extracting with methylene chloride, drying, evaporating the solvents, recrystallizing from ether, separating, drying and 334 mg of expected product is collected.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[C:12]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[C:18]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:17][C:13]=2[N:14]=[CH:15][N:16]=1.[NH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41]>CN(C=O)C.C(OCC)(=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:12]3[C:11]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][OH:41])=[N:16][CH:15]=[N:14][C:13]=3[O:17][C:18]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: NCCCCCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCCO)c23)cc1
Yield: 29.1 %

Procedure:
Add 1.15 g (8.9 mmol) DIEA to 1.0 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 0.70 g (5.9 mmol) 6-aminohexanol in 10 ml DMF and heat for 4 h to 120° C. Then dilute the mixture with ethyl acetate, wash with water and dilute hydrochloric acid, dry, and concentrate by evaporation. Purify the residue by RP-HPLC (column: Gromsil 250 mm×40 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-34 min 5%→98% acetonitrile, 34-38 min 98% acetonitrile). 364 mg (29% of theor.) 6-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}hexan-1-ol is obtained as a yellow oil, which solidifies after standing for 2 days.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[O:21])[CH2:13][CH2:12]1
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: O=C(CCBr)N1CCc2ccccc2C1
Product: Cl
Product: O=C(CCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1)N1CCc2ccccc2C1

Procedure:
from 7-chloro-3-(piperidin-4-yl)-1H-indole and 3-bromo-1-(3,4-dihydro-1H-isoquinolin-2-yl)propan-1-one. 1H NMR (DMSO-d6): 2.05-2.25 (m, 4H); 2.80 (t, 0.8H); 2.95 (t, 1.2H); 3.00-3.20 (m, 5H); 3.30-3.45 (m, 2H); 3.55-3.65 (m, 2H); 3.65-3.75 (m, 2H); 4.65 (s, 1.2H); 4.75 (s, 0.8H); 7.00 (t, 1H); 7.15-7.25 (m, 6H); 7.70 (d, 1H); 10.70 (broad s, 1H); 11.30 (s, 1H). MS m/z: 422 (MH+), 247.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][CH2:7][N:8](C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:29]([N:31]([CH2:58][CH3:59])[C:32]1[N:37]=[C:36]([C:38]2[O:42][N:41]=[C:40]([C:43]3[CH:48]=[C:47](C)[C:46](OC[C@@H]4CO4)=[C:45](CC)[CH:44]=3)[N:39]=2)[CH:35]=[C:34]([CH3:57])[N:33]=1)[CH3:30]>CN(C=O)C.CCOC(C)=O>[CH2:29]([N:31]([CH2:58][CH3:59])[C:32]1[N:37]=[C:36]([C:38]2[O:42][N:41]=[C:40]([C:43]3[CH:48]=[CH:47][C:46]([CH2:6][CH2:7][NH:8][C:1](=[O:5])[CH2:2][OH:3])=[CH:45][CH:44]=3)[N:39]=2)[CH:35]=[C:34]([CH3:57])[N:33]=1)[CH3:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CO
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OC[C@@H]1CO1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)c1nc(C)cc(-c2nc(-c3ccc(CCNC(=O)CO)cc3)no2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
To a solution of glycolic acid (33 mg, 0.43 mmol) and DIPEA (146 μL, 0.85 mmol) in DMF (5 mL) is added EDC (82 mg, 0.43 mmol) followed by HOBt (58 mg, 0.43 mmol). The reaction mixture is stirred at rt for 10 min before adding Intermediate 12 (100 mg, 0.28 mmol). Stirring is continued for 18 h and the reaction mixture is then diluted with EtOAc, washed with sat. aq. NaHCO3, dried over MgSO4, filtered and evaporated. The residue is purified by prep. TLC (eluting with DCM/7M NH3 in MeOH 10:1) to give the title compound (50 mg) as a yellow solid; tR=1.05 min; [M+H]+=411.75.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH3:9][O:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:9][O:10][C:11](=[O:27])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N:19]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCCBr
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCCN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1C(=O)OC
Temperature: 55 °C

Procedure:
Add methyl 4-bromobutyrate (54.4 mL, 0.437 mol) to a mixture of 2-tert-butoxycarbonylamino-4-chloro-benzoic acid methyl ester (96.15 g, 0.337 mol) and Cs2CO3 (274.10 g, 0.841 mol) in DMF (1.3 L). Heat the suspension at 55° C. overnight. Remove DMF under vacuum. Dilute the organics with ethyl acetate (1.5 L) and water (1.5 L). Separate the organic layer and extract the aqueous with ethyl acetate (2×0.5 L). Combine the organics and wash with half saturated potassium bicarbonate (1 L), water (2×0.5 L) and brine (0.5 L). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. This provides the title compound as a yellow oil crude (141.8 g):
Reaction SMILES: C(O[C:4](=[O:22])[CH:5]=[C:6]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[F:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>O>[Cl:20][C:16]1[C:15]([F:21])=[C:14]2[C:19]([C:4](=[O:22])[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:13]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C=C(Nc1cccc(Cl)c1F)c1ccccc1
Solvent: O
Product: O=c1cc(-c2ccccc2)[nH]c2c(F)c(Cl)ccc12
Temperature: 175 °C
Reaction time: 0.67 h

Procedure:
3-(3-Chloro-2-fluoro-phenylamino)-3-phenyl-acrylic acid ethyl ester (9.2 g, 0.029 mole) and polyphosphoric acid (160 mL, 3.0 mole) were combined and mechanically stirred under nitrogen at 175° C. external temperature for 40 minutes. While still hot, the reaction was poured over 800 mL of stirring ice-water rinsing with water. The mixture was a fine suspension, and was allowed to stir overnight. After stirring overnight, the mixture was filtered to collect the solid. The solid was washed with 4×150 mL water, and then with 4×150 mL of 4:1 ether/methanol. The solid was placed in the vacuum oven at 45° C. for 4 h and afforded the title compound as an off white product; 1H NMR (DMSO-d6, 400 MHz) δ 6.58 (bs, 1H), 7.50-7.54 (d of d, 1H, J=6.6 Hz & J=8.9 Hz), 7.60-7.64 (m, 3H), 7.82-7.84 (m, 2H), 8.07-8.09 (d of d, 1H, J=1.5 Hz & J=8.7 Hz); MS (ES+): 274.03 (100) [MH+], 275.99 (30) [(M+2)H+]. LCMS tR=2.97 min (OpenLynx, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[CH2:16][C:17](O)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([C:11]#[N:12])([CH3:10])[CH3:9].C1N=CN(C(N2C=NC=C2)=O)C=1.C([O-])(=O)[CH2:39][C:40]([O-])=[O:41]>C(C(C(OC(C)(C)C)=O)C(OC)=O)C.CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][C:17](=[O:18])[CH2:39][C:40](=[O:41])[O:20]2)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:10])([CH3:9])[C:11]#[N:12]
Reactant: O=C([O-])CC(=O)[O-]
Reactant: CC(C)(C#N)c1ccc(C=CC(O)(CC(=O)O)C2CCCC2)cc1Cl
Agent: CCC(C(=O)OC)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Temperature: 42 °C
Reaction time: 2 h

Procedure:
5-[3-Chloro-4-(cyano-dimethyl-methyl)-phenyl]-3-cyclopentyl-3-hydroxy-pent-4-enoic acid, from step 1 above, was dissolved in methyl tert-butyl ethylmalonate (3 mL). 4-DMAP (0.16 g, 0.13 mmol) and CDI (0.27 g, 1.68 mmol) were added and the reaction mixture was stirred under argon for 2 hours. In a separate flask was placed magnesium-bis-monoethyl malonate (0.74 g, 2.58 mmol) was suspended in THF (3 mL) and the mixture was heated to 42° C. The acylimidazole solution was added via cannula to the malonate mixture and the reaction was heated to 42° C. for 2 hours. The solvent was removed in vacuo to give a residue that was partitioned between 1 N HCl and EtOAc. The organic layer was dried over MgSO4 and concentrated to a clear oil (0.56 g, 100%).
Reaction SMILES: [CH2:1]([Al](Cl)Cl)[CH3:2].[CH3:6][C:7]1[C:8](=[O:15])[CH:9]([CH3:14])[CH:10]([CH3:13])[CH2:11][CH:12]=1.[CH2:16]=[CH:17]C=C.Cl>C(Cl)Cl>[CH3:14][CH:9]1[CH:10]([CH3:13])[CH2:11][CH:12]2[C:1]([CH3:2])([CH2:16][CH:17]=[CH:6][CH2:7]2)[C:8]1=[O:15]
Reactant: CC[Al](Cl)Cl
Reactant: C=CC=C
Reactant: CC1=CCC(C)C(C)C1=O
Agent: Cl
Solvent: ClCCl
Product: CC1CC2CC=CCC2(C)C(=O)C1C
Temperature: 25 °C
Reaction time: 360 h

Procedure:
In a 1 liter round-bottomed flask, at room temperature, were successively added CH2Cl2 (400 ml), BHT (100 mg) and a 1 M solution of EtAlCl2 in hexanes (80 ml; 0.08 mol). 2,5,6-trimethylcyclohex-2-en-1-one (55.2 g, 0.4 mol, 3:2 mixture of two isomers) was added dropwise, while maintaining the internal temperature below 30° C. Then butadiene (43.2 g, 0.8 mol) was added in one portion. The reaction was stirred at room temperature for 15 days. The reaction was then poured onto cold 5% aqueous HCl and extracted twice with ether. The organic layers were washed with saturated aqueous NaHCO3, water and brine and dried over solid sodium sulfate. The crude product was distilled to give 50 g of a liquid which was then chromatographed on silicagel (heptane:ethyl acetate 49:1) then purified by bulb-to-bulb distillation (B.P.=90° C./0.021 mbar) to give the totle compound (39.43 g, 0.205 mol, 51%) as a 3:2 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH:7]([CH3:20])[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([N:8]1[CH:7]([CH3:20])[CH2:6][C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[N:9]1)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: CC1Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Product: CC(C)NC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)ccc2CC1C
Yield: 53 %

Procedure:
0.6 g (1.9 mmoles) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 5, Step D or in Example 36, starting compound) are reacted with isopropyl isocyanate according to the method of Example 44. The crude product is recrystallized from ethanol. Thus, 0.4 g (53%) of the title compound are obtained. M.p.: 172°-174° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH2:18])[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2].[OH:21][C:22]1([CH2:29][C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.C(Cl)Cl>>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:19])[C:14]=2[NH:18][C:30](=[O:31])[CH2:29][C:22]2([OH:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]1=[O:20])[CH3:7])(=[O:3])[CH3:2]
Reactant: O=C(O)CC1(O)CCCCCC1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)CC3(O)CCCCCC3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (100.00 mg, 0.36454 mmol), 2-(1-hydroxycycloheptyl)acetic acid (75.3 mg, 0.437 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (346 mg, 0.911 mmol), N,N-diisopropylethylamine (0.159 mL, 0.911 mmol), N,N-dimethylformamide (2 mL, 30 mmol) and methylene chloride (8 mL, 100 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken onto the next step without further purification.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][OH:18]>>[C:1]([N:9]1[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Agent: Cl
Product: O=C(c1ccccc1)N1CCC(=NO)CC1

Procedure:
1-Benzoyl-piperidin-4-one oxime was prepared from 1-benzoyl-piperidin-4-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (1H, br. s.), 7.29-7.54 (5H, m), 3.49-3.81 (4H, m), 2.44-2.66 (2H, m), 2.17-2.42 (2H, m).