Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[F:14].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]3[CH2:36][C@H:35]4[C@:37]5([CH2:41][N:40]([CH2:42][C:43]([F:46])([F:45])[F:44])[S:39](=[O:48])(=[O:47])[NH:38]5)[C@H:32]([CH2:33][CH2:34]4)[CH2:31][C:30]=3[CH:49]=2)O1>>[F:7][C:8]1[CH:9]=[C:10]([N:5]2[CH:6]=[C:2]([C:26]3[CH:27]=[CH:28][C:29]4[CH2:36][C@H:35]5[C@:37]6([CH2:41][N:40]([CH2:42][C:43]([F:46])([F:45])[F:44])[S:39](=[O:47])(=[O:48])[NH:38]6)[C@H:32]([CH2:33][CH2:34]5)[CH2:31][C:30]=4[CH:49]=3)[N:3]=[CH:4]2)[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1ccc(F)c(F)c1
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4ccc(F)c(F)c4)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 3,4-difluorophenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].[CH2:27]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39](O)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.N1C=CC=CC=1.CN(C)C=O>[CH2:27]([C:30]1[CH:31]=[CH:32][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([O:25][C:24]([C@H:21]3[CH2:20][CH2:19][C@H:18]([C@H:15]4[CH2:16][CH2:17][C@H:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]4)[CH2:23][CH2:22]3)=[O:26])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1)[CH2:28][CH3:29]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: CCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O[C@H]3CC[C@H](c4ccc(CCC)cc4)CC3)CC2)CC1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A solution of 0.902 ml of dimethylformamide in 20 ml of acetonitrile was placed at -20° C. while gassing with argon in a sulphonation flask fitted with a mechanical stirrer, serum cap, thermometer and dropping funnel and treated within 2 minutes with 0.338 ml of oxalyl chloride. After completion of the addition, the mixture was stirred at -20° C. for a further 20 minutes and then 1.0 g of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarboxylic acid was introduced into the resulting white suspension via a solid substance addition tube. The mixture was subsequently stirred at -20° C. for 30 minutes and then treated dropwise at -20° C. within 10 minutes with a solution of 1.97 g of trans-4-(p-propylphenyl)cyclohexanol and 0.9 ml of pyridine in 20 ml of acetonitrile. The mixture was stirred for a further 15 hours while slowly warming to room temperature, then poured into 200 ml of cold 2N sodium carbonate solution and extracted three times with 200 ml of methylene chloride each time. The organic phases were washed once with 100 ml of 2N sodium carbonate solution and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (2.6 g) on 140 g of silica gel using toluene/hexane (volume ratio 1:1) gave 757 mg (44%) of trans-4-(trans-4-pentylcyclohexyl)cyclohexanecarboxylic acid trans-4-(p-propylphenyl)cyclohexyl ester as colourless crystals. A single recrystallization from acetone yielded analytically-pure product of m.p. (C-S) 63.3° C., phase transition S-N 241.5° C., cl.p. (N-I) 285.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>ClCCl.C(OCC)(=O)C>[C:20]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[CH:4][CH:3]=1)(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc(Cl)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(Cl)c2ccccc12
Yield: 68 %

Procedure:
To a stirred solution of 1-amino-4-chloronaphthalene (0.70 g, 3.9 mmol) in dichloromethane (50 ml) was added triethylamine (1.0 ml, 7 mmol), followed by propionyl chloride (0.5 ml, 5.8 mmol). After 20 min the mixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl (100 ml) followed by saturated sodium carbonate (100 ml). The organic phase was separated, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with a mixture of ethyl acetate and heptane, 130 ml, 3:10) to give 0.62 g (67%) of the desired compound as a white solid.
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:16][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC#CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCC#CCBr

Procedure:
1-Bromo-2-tridecyne (colorless oil) was prepared from 2-tridecyn-1-ol using the CBr4/triphenylphosphine mixture in dichloromethane to carry out the halogenation. 1-Bromo-2-tridecyne (colorless oil) was thus formed with a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:9]=[O:10])[CH:3]=1.[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:23]3[S:22][C:21]([C:19]([NH:18][C@@H:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])=[N:25][CH:24]=3)=[CH:27][CH:28]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: O=C=Nc1cccc(Cl)c1
Product: COC(=O)[C@@H](NC(=O)c1ncc(-c2ccc(NC(=O)Nc3cccc(Cl)c3)cc2)s1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 9, using 1-chloro-3-isocyanatobenzene and intermediate 2. 1HNMR (DMSO-d6, 300 MHz): δ 9.337 (s, 1H), 8.741-8.713 (d, 2H), 8.362 (s, 1H), 8.203-8.144 (t, J=8.7, 9 Hz, 1H), 7.744-7.716 (d, J=8.4 Hz, 2H), 7.581-7.552 (d, J=8.7 Hz, 2H), 7.507-7.463 (d, J=2.7, 11.1 Hz, 1H), 7.266-7.237 (d, J=3.7 Hz, 2H), 4.350-4.299 (t, J=7.5, 7.8 Hz, 1H), 3.681 (s, 3H), 2.306-2.238 (m, 1H), 0.965-0.923 (d, J=6.3 Hz, 6H); MS (ESI) m/z 485 (M−H), 487 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]C(=O)N(C)C)=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Br[CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CN(C)C(=O)Sc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(SCC(=O)C(C)(C)C)cc3)c2CC1
Yield: 30 %

Procedure:
Dissolve 3-(tert-butoxycarbonyl)-7-chloro-6-(4-dimethylcarbamoylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (57 mg, 0.1 mmol) in methanol (5 mL). Add potassium hydroxide (65 mg, 1.1 mmol) and heat the mixture for 3 h at 65° C. Then add 1-bromo-3,3-dimethyl-2-butanone and heat at 65° C. for 2 h. Cool the mixture and dilute with EtOAc. Wash the organic phase with water, dry over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/diethyl ether (7:3) to obtain the desired intermediate as an oil (18 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:15][NH2:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1.[N:17]1[CH:22]=[C:21]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH:20]=[N:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1)[CH2:15][NH:16][C:27](=[O:28])[C:26]1[CH:25]=[CH:24][C:23]([C:21]2[CH:20]=[N:19][CH:18]=[N:17][CH:22]=2)=[CH:31][CH:30]=1
Reactant: Cc1cc(-c2ccc(CN)cc2F)ccn1
Reactant: O=C(O)c1ccc(-c2cncnc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(-c4cncnc4)cc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanamine 15-3 (10.8 mg, 0.05 mmol), 4-(pyrimidin-5-yl)benzoic acid 15-4 (10.0 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-4-(pyrimidin-5-yl)benzamide 15 as a white powder. MS m/z 399.2 (M+1).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=O)[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl.[F:19][C:20]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:21]=1[CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([N:26]2[CH2:27][CH2:28][C:23]([CH2:22][C:21]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:20]=3[F:19])([OH:29])[CH2:24][CH2:25]2)=[O:11])[C:4]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccnc1-c1ccncc1
Reactant: OC1(Cc2ccc(F)cc2F)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1-c1ccncc1)N1CCC(O)(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A suspension of 2,4′-bipyridine-3-carboxylic acid dihydrochloride (0.30 g), 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.38 g), HATU (0.63 g) and triethylamine (0.77 mL) in DMF (4.0 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (0.30 g).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([S:21]C2C=CC=CC=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br-:28].[Al+3].[Br-].[Br-].Br>CCCCCC.CC(C)=O>[Br-:28].[C:1]1([S+:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][C:12]([S:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: Br
Agent: [Al+3]
Agent: [Br-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: c1ccc(Sc2ccc([S+](c3ccccc3)c3ccccc3)cc2)cc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
In 200 ml of n-hexane were suspended 6.07 g (0.03 mol) of diphenylsulfoxide and 11.2 g (0.06 mol) of diphenylsulfide, and 48.0 g (0.18 mol) of aluminum bromide was added thereto at 20 to 40° C., followed by reacting at 60 to 65° C. for 6 hours with stirring. After completion of the reaction, the reaction solution was poured into 500 ml of 12% hydrobromic acid, followed by washing with 200 ml of n-hexane five times and extracting with 200 ml of dichloromethane. The obtained dichloromethane layer was washed with 200 ml of water five times, followed by concentration under reduced pressure to obtain a crude product. Then, 120 ml of acetone was added to the crude product to dissolve at 55° C., followed by cooling to 5° C. to obtain crystal. The crystal was filtered off to obtain 5.3 g (Yield: 39%) of dipheny-4-phenylthiophenylsulfonium bromide as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:28][CH2:27][C@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: OC[C@H]1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3CO)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into an 8-mL sealed tube, was placed a solution of methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (150 mg, 0.50 mmol, 1.00 equiv), (R)-pyrrolidin-2-ylmethanol (150 mg, 1.49 mmol, 3.00 equiv), and potassium carbonate (345 mg, 2.50 mmol, 5.00 equiv) in Tol/DMSO (2.5/0.5 mL). The resulting mixture was stirred overnight at 100° C. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:50). This resulted in 120 mg (63%) of (R)-methyl 3-(2-(hydroxymethyl)pyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[S:1][C:2]2[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=2[O:11]1
Reactant: O=[N+]([O-])c1ccc(O)c(S)c1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)SC(c1ccc(Cl)cc1Cl)O2
Reaction time: 2 h
Yield: 18.7 %

Procedure:
2-Mercapto-4-nitrophenol (2.0 g) and 2,4-dichlorobenzaldehyde (2.0 g) were heated under reflux for 6 hours in toluene (70 ml) containing a catalytic amount (0.2 g) of p-toluenesulphonic acid monohydrate. Water formed in the reaction was separated by means of a Dean-Stark apparatus. The resulting reaction mixture was evaporated under reduced pressure, and the residue extracted with cyclohexane. The cyclohexane solution was then evaporated and the residue chromatographed on silica gel using methylene chloride/5% (v/v) methanol as eluant. The material obtained at this stage was contaminated with unreacted aldehyde. This was removed by stirring a methylene chloride solution of the crude product with 30% aqueous sodium bisulphite for 2 hours and then washing the solution successively with saturated sodium bicarbonate solution and water. After drying over anhydrous sodium sulphate, the methylene chloride was removed under reduced pressure. Crystallisation of the residue afforded the pure product as pale yellow crystals (0.7 g, 21%), mp 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH:30]1([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]1.CC(C)([O-])C.[Na+].CCCCCC>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:35][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:28])[CH3:26])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Reactant: OC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 70 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A solution of 6-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), cyclopentanol (1.1 equiv), and sodium tert-butoxide (1 equiv) in 1,4-dioxane (0.22 M) was taken in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed and the mixture was stirred at 70° C. for 3 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and loaded onto a silica column (packed with hexane). The column was eluted with 0-30% ethyl acetate in hexane. The fractions containing product were combined and concentrated to dryness to give the target product as a light yellow oil (Yield: 88%) that solidified upon standing. MS (ESI) m/z 499.4 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:23][CH2:22]4)[CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:28])[N:11]3[C:24]([O:26][CH3:27])=[O:25])[CH2:2]1.[CH:29](=O)[CH3:30]>>[CH:21]1([N:19]2[CH:20]=[C:16]([C:15]3[C:6]([O:5][CH:3]4[CH2:2][N:1]([CH2:29][CH3:30])[CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:24]([O:26][CH3:27])=[O:25])[C@@H:10]([CH3:28])[CH2:9][CH2:8]4)[CH:17]=[N:18]2)[CH2:22][CH2:23]1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(OC3CNC3)c2CC[C@@H]1C
Reactant: CC=O
Product: CCN1CC(Oc2c(-c3cnn(C4CC4)c3)ccc3c2CC[C@H](C)N3C(=O)OC)C1

Procedure:
(S)-Methyl 6-(1-cyclopropyl-1H-pyrazol-4-yl)-5-(1-ethylazetidin-3-yloxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from (S)-methyl 5-(azetidin-3-yloxy)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate and acetaldehyde according to the procedure outlined above for Example 40. 1H NMR (400 MHz, CD3OD) δ ppm 0.96 (t, J=7.20 Hz, 3H), 1.05-1.20 (m, 7H), 1.42-1.55 (m, 1H), 2.15-2.25 (m, 1H), 2.40-2.52 (m, 3H), 2.81-2.95 (m, 1H), 3.01-3.15 (m, 2H), 3.41-3.52 (m, 2H), 3.68-3.71 (m, 1H), 3.78 (s, 3H), 4.21-4.28 (m, 1H), 4.51-4.61 (m, 1H), 7.20-7.32 (m, 2H), 7.76 (s, 1H), 7.99 (s, 1H). MS (ESI, pos. ion) m/z 411 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[CH2:15])[C:8]1=[O:16])=[O:5])C.[C:17]([CH2:20]N1CCCCCC(=C)C1=O)(O)=[O:18].[S:31]1C=CC=C1CC(O)=O>>[C:4]([CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:15][S:31][C:17](=[O:18])[CH3:20])[C:8]1=[O:16])([OH:3])=[O:5]
Reactant: C=C1CCCCCN(CC(=O)O)C1=O
Reactant: C=C1CCCCCN(CC(=O)OCC)C1=O
Reactant: O=C(O)Cc1cccs1
Product: CC(=O)SCC1CCCCCN(CC(=O)O)C1=O

Procedure:
Hydrolyze 100 mg 1-ethoxycarbonylmethyl-3-methyleneperhydroazocin-2-one (prepared as in Example 1) with base as described in Example 3. Treat the resulting 1-carboxymethyl-3-methyleneperhydroazocin-2-one with thiolacetic acid as described in Example 3 and isolate the desired 1-carboxymethyl-3-acetylthiomethylperhydroazocin-2-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:37][N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CO>[CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)[C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:38][CH3:37])=[O:18])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)O)c2)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C(=O)NC)c2)N2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a solution INTERMEDIATE 9 (0.120 mg, 0.25 mmol)) in 2 ml of DMF was added HATU (0.132 mg, 0.35 mmol) and diisopropylethylamine (173 μL, 0.99 mmol). The reaction was stirred for 30 minutes, after which was added (250 μL, 0.50 mmol) of 2 N HNCH3 in MeOH and the stirring continued over night. The reaction was concentrated and partitioned between a saturated solution of NaHCO3 and ethyl acetate. The organic layer was separated and the aqueous layer extracted 5 times with ethyl acetate. The organic layers were dried (MgSO4), filtered and concentrated to yield COMPOUND 3. 1H NMR (400 NM, CD3OD): δ 1.07 (m, 3H), 1.21 (m, 3H), 2.32 (m, 2H), 2.90 (s, 3H), 3.02 (m, 2H), 3.24 (m, 4H), 3.40 (m, 2H), 3.50 (m, 2H), 4.34 (s, 2H), 4.55 (s, 1H), 7.33 (d, J=8.2 Hz, 2 H), 7.41 (m, 1H), 7.48 (m, 5H), 7.56 (d, J=8.2 Hz, 2H), 7.63 (m, 2H), 7.93 (m, 1H)
Reaction SMILES: O1CCCC1.[Br-].[F:7][C:8]([F:13])([F:12])[C:9]([Zn+])=[CH2:10].Br[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][CH:23]([F:25])[F:24])=[C:17]([Cl:26])[CH:16]=1.O>CN(C)C=O>[Cl:26][C:17]1[CH:16]=[C:15]([C:9]([C:8]([F:13])([F:12])[F:7])=[CH2:10])[CH:20]=[C:19]([Cl:21])[C:18]=1[O:22][CH:23]([F:25])[F:24]
Reactant: FC(F)Oc1c(Cl)cc(Br)cc1Cl
Reactant: C=C([Zn+])C(F)(F)F
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(OC(F)F)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 21 mL of a 1M tetrahydrofuran solution of 1-trifluoromethylethenyl zinc bromide prepared according to a method described in the literatures, a solution of 2.4 g of 4-bromo-2,6-dichloro(difluoromethoxy)benzene in 12 mL of N,N-dimethylformamide was added, and tetrahydrofuran was distilled off under reduced pressure. To the remaining N,N-dimethylformamide solution, 0.23 g of dichlorobis(triphenylphosphine) palladium (II) was added and the resultant mixture was stirred at 100° C. for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and charged into 100 mL of water and the resultant mixture was extracted with diethyl ether (100 mL×1). The organic phase was washed with water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 1.8 g of the objective substance as a brown oily substance.
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]1[CH:5]=[CH:6][C:7]2[O:14]C(=O)[CH2:11][CH2:10][C:8]=2[CH:9]=1.CC[O:17][CH2:18][CH3:19]>>[OH:14][C:7]1[CH:6]=[CH:5][CH:4]=[CH:9][C:8]=1[CH2:10][CH2:11][C:18]([CH3:19])([OH:17])[CH3:1]
Reactant: O=C1CCc2ccccc2O1
Reactant: CCOCC
Reactant: C[Mg]Br
Product: CC(C)(O)CCc1ccccc1O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To an ice-cooled solution of methyl magnesium bromide in ether (104 ml × 2.7M; 0.28 mole) was added slowly, under nitrogen, a solution of 13.8 g (0.093 mole) of dihydrocoumarin (Compound 28, Scheme 8) in 230 ml of dry ether. The cooling bath was then removed and the mixture stirred for a further 16 hours. The reaction mixture was then poured onto 300 g of ice and 10 ml of conc. H2SO4 and the mixture was stirred to ensure dissolution. The organic layer was then separated and the aqueous layer was extracted with 2×100 ml of ether. The organic layers were combined and washed successively with 70 ml portions of water, saturated NaHCO3, 2M Na2S2O3 and saturated NaCl and then dried (Na2SO4). The solution was then filtered and the filtrate concentrated in-vacuo to give the title compound as a white solid. PMR (CDCl3) : & 1.30 (6H, s), 1.80 (2H, t, J~7.5 Hz), 2.12 (1H, broad s), 2.73 (2H, t, J~7.5 Hz), 6.80-6.87 (2H, m), 7.00 (1H, broad s), 7.07-7.14 (2H, m).