Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[B:6]([O:15][CH:16]([CH3:18])[CH3:17])([O:11]C(C)C)[O:7]C(C)C.[ClH:19]>C1(C)C=CC=CC=1.C1COCC1.O>[Cl:19][C:3]1[CH:4]=[CH:17][C:16]([O:15][B:6]([OH:7])[OH:11])=[CH:18][CH:2]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]CCCC
Reactant: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: OB(O)Oc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-bromophenyl (70.6 g) was dissolved in a mixture of toluene (588.3 ml) and THF (147 ml) under argon, and n-BuLi (176.4 ml, 2.5M in hexane) was added dropwise at −78° C., stirred for 1 hours, then tri-isopropyl borate (109.2 ml) was added dropwise at −78° C., stirred for 1 hour. HCl (360.4 ml, 2.2 mol/l) was added at −20° C., and warmed to 110° C., the reaction was diluted with water, the aqueous layer was extracted with toluene (35 ml, twice). The extract and the organic layer were washed with saturated brine, dried over anhydrous Na2SO4 over night. The organic layer was concentrated under reduced pressure to give 4-chlorophenylboric acid (48 g) as a solid after crystallization (toluene).
Reaction SMILES: [CH3:1][OH:2].OC1C=C[C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16](O)=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=CC=1.BrBr.[OH:22]O>[Fe].O>[CH3:12][C:10]([C:13]1[CH:14]=[CH:15][C:16]([C:1]([OH:22])=[O:2])=[CH:17][CH:18]=1)([CH3:7])[CH3:11]
Reactant: OO
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CO
Agent: [Fe]
Agent: BrBr
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)cc1

Procedure:
A high purity 4,4′-isopropylidine-bis-(2,6-dibromophenol) characterised by ionic bromides less than 10 ppm, colour in alkaline solution from 60-100 HU, HPLC purity about 99.9%, APHA of 20% MeOH solution less than 10.0 HU, Fe less than 1.0 ppm, turbidity of 20% MeOH solution less than 5 NTU, pH of 10% slurry 6.0-7.0, size of the crystal particles, 250 to 280 microns with angle of repose lower than 30°. The product is produced by reacting Bisphenol-A with bromine in a “water-immiscible” polar solvent in the presence of hydrogen peroxide, aging the reaction products after the reaction, eliminating the excess bromine by reducing agents, washing the product layer with a combination of anionic surfactant, alkali, reducing agent and demineralised water under controlled pH conditions, partially distilling the organic solvent chilling the medium containing the product, filtering the crude product, boiling the crude product with alkali, reducing agent and demineralised water, filtering the TBBA, washing the product with demineralised water and drying to obtain the final high purity TBBA with high yield.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH3:14][O:15][CH2:16]Cl.O>CN(C=O)C>[CH3:14][O:15][CH2:16][O:13][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:10][CH2:9][CH2:8]2
Reactant: O=[N+]([O-])c1cc2c(cc1O)CCC2
Reactant: COCCl
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
1.04 g of 55% sodium hydride/paraffin oil was suspended in 40.0 mL of DMF, and a solution of 3.90 g of 6-nitroindan-5-ol in DMF (10.0 mL) was added dropwise thereto at 5° C. over 15 minutes, followed by stirring at 5° C. for 30 minutes. To the reaction liquid was added dropwise 2.15 mL of methoxymethyl chloride over 5 minutes, followed by stirring at room temperature for 1 hour. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 80:20) to obtain 4.20 g of 5-(methoxymethoxy)-6-nitroindane.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(-c3nnn(C)n3)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnc(-c2ccc3scc(CBr)c3c2)n1
Yield: 74.1 %

Procedure:
To a refluxing mixture of 3-methyl-5-(2-methyltetrazol-5-yl)benzo[b]thiophene (0.162 g, 0.703 mmol) and benzoyl peroxide (10.6 mg) in carbon tetrachloride (10 ml) irradiated with two desk lamps (2×60 W) was added N-bromosuccinimide (0.126 g, 0.707 mmol) in small portions. After the addition was complete the mixture was heated at reflux for a further 90 min, then filtered and the filtrate was evaporated in vacuo to leave an oil/solid mixture. Chromatography on flash silica, eluting with dichloromethane gave 0.161 g of crude 3-bromomethyl-5-(2-methyltetrazol-5-yl)benzo[b]thiophene as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH:7]=[C:8]([P:12](=[O:21])([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])[C:9]([CH3:11])=O)([O-:3])=[O:2].[NH2:25]/[C:26](/[CH3:37])=[CH:27]\[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[O:29]>C(O)(C)C>[CH3:37][C:26]1[NH:25][C:9]([CH3:11])=[C:8]([P:12]([O:17][CH:18]([CH3:20])[CH3:19])([O:13][CH:14]([CH3:16])[CH3:15])=[O:21])[CH:7]([C:6]2[CH:22]=[CH:23][CH:24]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:27]=1[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH3:36])=[O:29]
Reactant: CCCOCCOC(=O)/C=C(/C)N
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)P(=O)(OC(C)C)OC(C)C
Solvent: CC(C)O
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C(P(=O)(OC(C)C)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 71.5 %

Procedure:
A mixture of 5.1 grams of diisopropyl 1-(3-nitrobenzylidene)-acetonylphosphonate and 2.69 grams of 2-n-propoxyethyl 3-aminocrotonate was added to 20 ml of isopropanol and the mixture was heated to reflux for eight hours with stirring. The reaction mixture was evaporated in vacuo, to the residue was added ether to crystallize, the crystals were collected by filtration, and recrystallized from a mixture of ethyl acetate and ether to afford 5.38 grams of 2-n-propoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-diisopropoxyphosphinyl-1,4-dihydropyridine-3-carboxylate, pale yellow crystals, melting point 125°-6° C. Yield 72%.
Reaction SMILES: [C:1](/[C:3](/[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[CH:4]\[C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([O-])=[O:21])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)#[N:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH2:52]([N:54]([CH2:62][CH3:63])[C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][CH:56]=1)[CH3:53]>C(Cl)Cl>[CH2:62]([N:54]([CH2:52][CH3:53])[C:55]1[CH:60]=[CH:59][C:58]([NH:61][C:20](=[O:21])[CH2:19][CH2:18][C:17]([O:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]3[S:9][C:5](/[CH:4]=[C:3](\[C:1]#[N:2])/[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=4)=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[O:23])=[CH:57][CH:56]=1)[CH3:63]
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(OC(=O)CCC(=O)[O-])CC3)s2)cc1OC
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCN(CC)c1ccc(NC(=O)CCC(=O)OC2CCN(c3ccc(/C=C(\C#N)c4ccc(OC)c(OC)c4)s3)CC2)cc1
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Compound 18 (500 mg) was dissolved in methylene chloride (10 mL), and 2-chloro-4,6-dimethoxy-1,3,5-triazine (224 mg) and N-methylmorpholine (129 μL) were added to the solution, followed by stirring with ice cooling for 30 minutes. Subsequently, N,N-diethyl-1,4-phenylenediamine (209 μL) and N methylmorpholine (215 μL) were added to the mixture, followed by stirring at room temperature for 17 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 322 mg, 49%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(O)C>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2s1
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc2sc(NCCN3CCCCC3)nc2c1

Procedure:
2-Chlorobenzothiazole (10 mmol), 10 mmol of 2-piperidinoethanamine, and 30 mmol of triethylamine in 50 ml of dry ethanol were refluxed for 6 hours. The product was crystallized with hydrochloric acid in 2-propanol and recrystallized in methanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6](=O)[CH2:7]Cl)[CH3:2].[NH2:18][C:19]([NH2:21])=[S:20].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:6]1[N:18]=[C:19]([NH2:21])[S:20][CH:7]=1)=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
209.2 g of 2-benzylidene-3-oxo-4-chlorobutyric acid ethyl ester (described in J. Amer. Chem. Soc. 66, 1933 (1944)), 63.2 g of thiourea and 104.6 g of sodium acetate were dissolved in a mixture of 1,460 ml of tetrahydrofuran and 630 ml of water. The solution was stirred overnight at room temperature and the tetrahydrofuran was then evaporated off. The aqueous phase was adjusted to pH 8 and extracted three times with ethyl acetate. Drying and evaporation of the organic phase gave a viscous oil, which chiefly consisted of the desired Z-isomer. The product was further processed in the crude form.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][N:16]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:17][CH2:18][CH2:19][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH2:48](Br)[CH:49]=[CH2:50]>CN(C=O)C>[CH2:50]([N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:23][CH2:22][CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:49]=[CH2:48]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NCCCN(CCCN(CCC1CCCCN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(CCCN(CCC1CCCCN1C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 1.13 g (1.758 mmol) of 1-[2-[(N-BOC)-2-piperidyl]-ethyl]-1,5,9-tri-BOC-1,5,9-triazanonane in 11.3 ml of DMF there are added, with stirring, 0.14 g (3.5 mmol) of sodium hydride dispersion (approximately 60%) and, after 10 minutes, 0.296 ml (3.5 mmol) of allyl bromide (Fluka, Buchs, Switzerland). The reaction mixture is stirred at room temperature for 15 hours and then a further 1/3 of the original amount of sodium hydride dispersion (approximately 60%) and a further 1/3 of the original amount of allyl bromide are added, the reaction mixture is stirred at room temperature for a further 24 hours and is then concentrated by evaporation in vacuo. The residue is partitioned between water and methylene chloride, and the organic phase is washed with brine, dried over sodium sulfate and concentrated by evaporation. After purification of the residue by flash chromatography on silica gel having a particle size of 0.04-0.063 mm using a hexane/tert-butyl methyl ether mixture (7:3), the title compound is obtained in the form of a resin, Rf value=0.34 (silica gel/methylene chloride:methanol (30:1)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][N:15]([CH2:24][C:25]3[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=3)[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1>[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[C:3]2[C:17]([C:18]#[C:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[CH:16][N:15]([CH2:24][C:25]3[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([CH3:34])=[CH:27][N:26]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: [Cl-]
Agent: [Zn+2]
Product: COc1c(C)cnc(Cn2cc(C#C[Si](C)(C)C)c3c(Cl)nc(N)nc32)c1C

Procedure:
The title compound was prepared by cleaving the pivaloyl protecting group of N-[4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-5-trimethylsilanylethynyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide with ZnCl2 according to the General Procedure B. tR=6.56 min. 1H NMR (CDCl3) δ 8.22 (s, 1H), 7.11 (s, 1H), 5.30 (s, 2H), 5.09 (s, 2H), 3.75 (s, 3H), 2.26 (s, 3H), 2.18 (s, 3H), 0.24 (s, 9H).
Reaction SMILES: [Li]CCCC.[C:6]([Si:10]([O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH3:22])([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].CN(CCN(CCN(C)C)C)C.[CH3:35][N:36]1[C:40]([CH:41]=[O:42])=[N:39][C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:37]1>C1COCC1.O>[Si:10]([O:13][C:14]1[C:15]([CH2:21][CH3:22])=[CH:16][C:17]([CH:41]([C:40]2[N:36]([CH3:35])[N:37]=[C:38]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:39]=2)[OH:42])=[C:18]([F:20])[CH:19]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11]
Reactant: Cn1nc(-c2ccccc2)nc1C=O
Reactant: CCc1ccc(F)cc1O[Si](C)(C)C(C)(C)C
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1O[Si](C)(C)C(C)(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
BuLi (0.67 mL, 1.6 M in hexanes, 1.1 mmol) was added dropwise to a solution of Intermediate 386.3 (250 mg, 0.98 mmol) and PMDTA (0.20 mL, 0.98 mmol) in THF (4 mL) at −78° C. The mixture was warmed to −40° C. and stirred for 30 min. After recooling the reaction to −78° C., Intermediate 386.1 (203 mg, 1.08 mmol) in THF (2 mL) was added and the mixture was warmed to ambient temperature over 2 h. Water was added to the mixture and it was extracted with EtOAc. The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 292 mg of Intermediate 386.4 as a clear oil. LCMS 442.34 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:43][CH2:44][CH:45]4[CH2:47][CH2:46]4)=[C:24]([NH:27][C:28](=[O:42])[CH:29]=[CH:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34][OH:35])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:43][CH2:44][CH:45]4[CH2:47][CH2:46]4)=[C:24]([NH:27][C:28](=[O:42])[CH:29]=[CH:30][CH2:31][N:32]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:33][CH2:34][O:35][C:1]([CH3:2])=[O:3])[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CCO
Solvent: ClCCl
Product: CCOC(=O)CN(CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1)CCOC(C)=O
Reaction time: 8 h

Procedure:
47 μl of acetic anhydride and catalytic amounts of 4-dimethyl-aminopyridine are added to 250 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxy-quinazoline in 2 ml of methylene chloride. The reaction mixture is stirred overnight at ambient temperatures and then evaporated to dryness. The crude product is purified by chromatography on a silica gel column with methylene chloride, followed by methylene chloride/methanol (9:1) as eluant. Yield: 150 mg (56% of theory), Melting point: 90-92° C. Mass spectrum (ESI+): m/z=614, 616 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH:16]1[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C>[F:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][N:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)cc(OCCN2CCC2)c1
Temperature: 30120 °C

Procedure:
1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.5 g, 1.6 mmol), azetidine (0.23 ml, 3.2 mmol) and potassium carbonate (0.58 g, 4.2 mmol) was dissolved in acetonitrile (10 ml). The mixture was heated in a sealed container at 30120° C. for 2 h. The reaction mixture was cooled to room temperature, CH2Cl2 (100 ml) was added, solids was filtered off and the volatiles were evaporated. The amine was converted to the fumaric acid salt and re-crystallized from methanol/diethyl ether. MS m/z (relative intensity, 70 eV) 273 (M+, 1), 94 (5), 82 (3), 71 (5), 70 (bp).
Reaction SMILES: [CH3:1]OC(C)(C)C.C[Zn]C.[Br:10]/[CH:11]=[C:12]1/[C@H:13]2[C@:17]([CH3:21])([CH2:18][CH2:19][CH2:20]/1)[C:16]([CH:22]=[O:23])=[CH:15][CH2:14]2>C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.[C@@H]1(NS(C(F)(F)F)(=O)=O)CCCC[C@H]1NS(C(F)(F)F)(=O)=O.C(OCC)(=O)C>[Br:10]/[CH:11]=[C:12]1\[CH2:20][CH2:19][CH2:18][C@@:17]2([CH3:21])[C@H:13]\1[CH2:14][CH:15]=[C:16]2[C@@H:22]([OH:23])[CH3:1]
Reactant: COC(C)(C)C
Reactant: C[C@]12CCC/C(=C\Br)[C@@H]1CC=C2C=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: C[Zn]C
Agent: O=S(=O)(N[C@@H]1CCCC[C@H]1NS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@H](O)C1=CC[C@H]2/C(=C/Br)CCC[C@]12C
Temperature: 50 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(1R)-trans-N,N′-1,2-cyclohexanediylbis(1,1,1-trifluoromethanesulfonamide) (2.3 mg, 0.006 mmol) was placed in a reaction vessel. After replacing the atmosphere with nitrogen, t-butyl methyl ether (0.03 ml) was added thereto and dissolved. To the solution, tetraisopropoxy titanium (0.0177 ml, 0.06 mmol) was added at room temperature, and the resulting mixture was heated at 50° C. for 30 minutes. After cooling to room temperature, dimethylzinc (1.0 M in heptane, 0.12 ml, 0.12 mmol) was added thereto. The obtained reaction mixture was added to (3aR,4E,7aS)-4-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-7a-methyl-3H-indene-1-carbaldehyde (Compound 29: 15.3 mg, 0.06 mmol). After stirring the reaction solution at room temperature for 1 hour, ethyl acetate (30 ml) was added thereto, and the resulting mixture was washed with 2N hydrochloric acid, saturated brine and with saturated aqueous sodium hydrogen carbonate solution, respectively. The organic layer was dried over sodium sulfate, and the solvent was evaporated to obtain the reaction mixture. The reaction mixture was purified by preparative TCL to obtain (S)-1-{(3aS,7E,7aR)-7-(bromomethylene)-3a,4,5,6,7,7a-hexahydro-3a-methyl-1H-indene-3-yl}ethanol (18.4 mg, 100%). The spectrum data thereof agreed with the data described in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:31]([S:35](Cl)(=[O:37])=[O:36])[CH2:32][CH2:33][CH3:34]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:35]([CH2:31][CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 120 °C
Yield: 29.2 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 1-butanesulfonyl chloride (26 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (8 mg, 29%). 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, J=7.35 Hz, 3 H) 0.98 (d, J=6.62 Hz, 6 H) 1.37 (m, 2 H) 1.56 (m, 2 H) 1.69 (m, 3 H) 3.19 (t, J=7.74 Hz, 2 H) 4.48 (t, J=7.74 Hz, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=9.01, 2.39 Hz, 1 H) 7.65 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.55 (dd, J=8.09, 1.84 Hz, 1 H) 8.89 (dd, J=4.41, 1.84 Hz, 1 H) 10.35 (s, 1 H) 14.07 (s, 1 H) 15.13 (s, 1 H). MS (ESI+) m/z 548 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([Li])([CH2:31]C)[CH3:30].C(Br)C=C>O1CCCC1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH2:18][CH2:31][CH:29]=[CH2:30])=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reactant: [Li]C(C)CC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of (2R)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamic acid tert-butyl ester (0.41 g, 1 mmole) in anhydrous tetrahydrofuran (20 mL) containing 10 mg of 1,10-phenanthroline at −40° C. was slowly added 2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent of s-butyl lithium had been added, the deep red color of the indicator became apparent. The reaction was allowed to stand for 1.5 hours, after which allyl bromide (0.24 g, 2.0 mmole) was added. The reaction was allowed to stand for an additional 4 hours and then was quenched with water (4 mL). The reaction mixture was next diluted with ether (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the solvent removed under vacuum. Column chromatography on silica gel (5% methylene chloride/hexane) afforded 0.37 g (75%) of the title compound as an oil, [α]25D=−32.42° (3.7, THF).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.C([O:18][C:19]([C:21]1[C:22]([O:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH:39]([NH2:43])[C:40]([OH:42])=[O:41])=[CH:34][CH:33]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])C.[OH-].[Na+]>CS(C)=O>[C:40]([CH:39]([NH:43][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:22]2[C:21]([C:19]([OH:20])=[O:18])=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:33][CH:34]=1)([OH:42])=[O:41]
Reactant: CCOC(=O)c1cc2ccccc2nc1Oc1ccc(CC(N)C(=O)O)cc1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Oc2nc3ccccc3cc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-[4-(2-amino-2-carboxy-ethyl)-phenoxy]-quinoline-3-carboxylic acid ethyl ester in DMSO to provide, after hydrolysis with aqueous NaOH, the title compound in good yield.