Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].O.[C:9]([OH:13])([CH3:12])([CH3:11])[CH3:10].[CH3:14][O:15][C:16](=[O:33])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C(Cl)Cl>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:24]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:16]([O:15][CH3:14])=[O:33])([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)(C)O
Reactant: COC(=O)Cc1ccccc1NCC(=O)OC(C)(C)C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1N(CC(=O)OC(C)(C)C)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.1 h

Procedure:
Chlorosulfonylisocyanate (1.42 mL, 16.4 mmol) is added to CH2Cl2 (20 mL) in a dry flask under argon balloon, and cooled with stirring in an ice/salt/water bath. t-Butanol (1.57 mL, 16.4 mmol) is added to this solution and stirred while maintaining the cooling for 1 h. Then a solution of the title C compound, [2-(t-butoxycarbonylmethyl-amino)-phenyl]-acetic acid methyl ester (3.84 g, 13.7 mmol) and TEA (5.7 mL, 41.1 mmol) in CH2Cl2 (90 mL) is rapidly cannulated into this above mentioned stirred, cooled solution. During 18 h the reaction slowly warms to RT, then concentrated and partitioned between EtOAc and 0.5N aqueous HCl (2×50 mL). The organic solution is washed with brine (25 mL), dried over anhydrous MgSO4, filtered and concentrated. The resulting residue is chromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 30:70 over 30 min, maintained at 30:70 for 15 min then to 50:50 over 6 min. Fractions containing product are combined and evaporated to give an oil which on standing in a high vacuum foamed to yield N-(t-butoxycarbonyl-sulfamoyl)-N-[2-(methoxycarbonylmethyl)-phenyl]-glycine t-butyl ester as a white foam: [M−1]−=457.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C@@H:10]([OH:15])[C:11]([F:14])([F:13])[F:12].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:49][C:50]([F:61])([F:60])[O:51][C:52]1[CH:53]=[C:54]([CH:57]=[CH:58][CH:59]=1)[CH:55]=O>CN(C=O)C>[F:14][C:11]([F:12])([F:13])[C@H:10]([OH:15])[CH2:9][N:8]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]([CH2:55][C:54]2[CH:57]=[CH:58][CH:59]=[C:52]([O:51][C:50]([F:49])([F:60])[F:61])[CH:53]=2)[CH2:17][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: Nc1ccccc1NC[C@@H](O)C(F)(F)F
Reactant: O=C(CBr)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O[C@H](CN1c2ccccc2N(Cc2cccc(OC(F)(F)F)c2)CC1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(R)-3-[(2-aminophenyl)amino]-1,1,1-trifluoropropan-2-ol (133 mg, 0.603 mmol) was dissolved in DMF (5024 μl). 2-Bromo-1-phenylethanone (100 mg, 0.502 mmol) and Hunig's Base (88 μl, 0.502 mmol) were added and the mixture was stirred at 25° C. for 4 hours. Sodium triacetoxyborohydride was added (639 mg, 3.01 mmol), and the reaction mixture was stirred at 25° C. for 12 hours. The reaction was heated to 80° C. for 2 hours, then was cooled to 25° C., and 3-(trifluoromethoxy)benzaldehyde (144 μl, 1.005 mmol) was added. The reaction mixture was stirred at 25° C. for 2 hours, and then was heated to 50° C. for 10 hours. The reaction mixture was quenched with saturated ammonium chloride solution and then was extracted into EtOAc. The organic phase was washed four times with water, then once with brine, then was dried with MgSO4, filtered, concentrated, and purified on a 40 g silica gel column with a 0-100% DCM/Hexanes gradient. (R)-1,1,1-trifluoro-3-{2-phenyl-4-[3-(trifluoromethoxy)benzyl]-3,4-dihydroquinoxalin-1(2H)-yl}propan-2-ol was isolated as a 10:3 (R:S) mixture of diastereomers. This mixture was purified with reverse phase C18 chromatography with a 50-100% MeCN/H2O gradient with 0.1% TFA modifier. Diastereomerically pure (R)-3-((R)-4-(3-trifluoromethoxy)-2-phenyl-3,4-dihydroquinoxalin-1(2H)-yl)-1,1,1-trifluoro-propan-2-ol was isolated. 1H NMR (400 MHz, CDCl3) δ 3.28 (dd, J=9.2, 2.8 Hz, 1H), 3.39 (dd, J=12.4, 8.0 Hz, 1H), 3.63 (dd, J=8.8, 2.8 Hz, 1H), 3.83 (d, J=12.4 Hz, 1H), 4.24 (d, J=8.8 Hz, 1H), 4.37 (d, J=8.8 Hz, 1H), 4.42 (m, 1H), 4.87 (s, 1H), 6.56 (d, J=6.4 Hz, 1H), 6.70 (m, 2H), 6.82 (m, 2H), 6.93 (d, J=6 Hz, 1H), 7.04 (d, J=6.4 Hz, 2H), 7.22 (m, 3H), 7.33 (m, 3H), MS m/z=497.28.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH:4](Br)[C:5](=O)[CH2:6][O:7][CH3:8].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[CH3:1][O:2][C:3]([C:4]1[S:14][C:13]([NH2:15])=[N:12][C:5]=1[CH2:6][O:7][CH3:8])=[O:11]
Reactant: COCC(=O)C(Br)C(=O)OC
Reactant: NC(N)=S
Solvent: CCO
Product: COCc1nc(N)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of the crude product (about 30 mmol) obtained in Step 1 and thiourea (2.28 g) in ethanol (60 ml) was heated under reflux overnight. After cooling to room temperature, the reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. Then, suitable amounts of isopropanol, chloroform, ethyl acetate and diisopropyl ether were added, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration and dried to give the title compound (3.27 g).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].F[C:22](F)(F)[C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[CH:25][N:24]=1.O>CN1C(=O)CCC1>[C:1]([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:30][CH2:29][C:26]3[CH:25]=[N:24][C:23]([CH3:22])=[CH:28][CH:27]=3)[C:9]3[CH2:14][CH2:15][N:16]([CH3:18])[CH2:17][C:8]=3[C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(CCn2c3c(c4cc(C(C)(C)C)ccc42)CN(C)CC3)cn1
Reaction time: 0.17 h
Yield: 10.1 %

Procedure:
To a solution of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (200 mg, 0.82 mmol) in NMP (3.0 ml), powdered KOH (462 mg, 8.23 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (286 mg, 1.65 mmol) was added slowly to the above solution and stirred for 14 h at 25 deg C. After completion of the reaction (monitored by LCMS), water (5 mL) was added to the crude and extracted with the ethylacetate. The organic layer was dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 30 mg of 8-tert-butyl-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole as TFA salt
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:39]([O:41][CH3:42])=[O:40])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:38])[NH:25][S:26]([C:29]1[C:36]([CH3:37])=[CH:35][C:33]([CH3:34])=[CH:32][C:30]=1[CH3:31])(=[O:28])=[O:27])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[NH:43]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C@H:44]([C:49](O)=[O:50])[C@H:45]([CH2:47][CH3:48])[CH3:46].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C.O1CCOCC1>[NH:43]([C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])[C@H:44]([C:49]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([NH:18][C@H:19]([C:39]([O:41][CH3:42])=[O:40])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:38])[NH:25][S:26]([C:29]1[C:30]([CH3:31])=[CH:32][C:33]([CH3:34])=[CH:35][C:36]=1[CH3:37])(=[O:27])=[O:28])=[O:17])[CH2:7][O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4])=[O:50])[C@H:45]([CH2:47][CH3:48])[CH3:46]
Reactant: COC(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C)NC(=O)[C@H](COCc1ccccc1)NC(=O)CN
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)NS(=O)(=O)c1c(C)cc(C)cc1C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The Boc group of product (XIII) was removed by the same method as described in regard to compound (XI) to give 0.40 g (0.63 mmol) of HCl.H-Gly-Ser(Bzl)-Arg(Mts)-OMe. It was then dissolved in a mixed solvent of 5.4 ml of rectified DMF and 5.4 ml of dioxane together with the equimolar amount (0.14 g) of Boc-Ile-OH. The resulting solution was stirred at 0° C. for 10 minutes and then 0.21 ml of DPPA and 0.20 ml of triethylamine were added. The mixture was stirred at room temperature for 24 hours. The solution thus obtained was freed from any acidic and alkaline materials in the same manner as described in regard to compounds (XII) and (XIII). After drying, 0.28 g of Boc-Ile-Gly-Ser(Bzl)-Arg(Mts)-OMe was obtained.
Reaction SMILES: C1([CH:7]([N:14]2[CH2:19][CH2:18]NCC2)[C:8]2[CH:13]=[CH:12]C=CC=2)C=CC=CC=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl.[CH2:25](N(CC)CC)C>CC(C)=O>[OH:24][C:23]1[CH:18]=[C:19]2[C:12]([CH:13]=[CH:8][CH:7]=[N:14]2)=[CH:20][C:22]=1[CH3:25]
Reactant: CCN(CC)CC
Reactant: ClCC1CO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CC(C)=O
Product: Cc1cc2cccnc2cc1O

Procedure:
In 50 ml of acetone were dissolved 5.04 g of diphenylmethylpiperazine and 5.5 g of epichlorohydrin, and 4.2 ml of triethylamine was then added thereto.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10](=O)[C:11]#[C:12][CH3:13])=[CH:6][C:5]=12.Cl.[NH2:16][OH:17].C(N(CC)CC)C>CN(C=O)C>[CH3:13][C:12]1[O:17][N:16]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)[CH:11]=1
Reactant: NO
Reactant: CC#CC(=O)c1ccn2ccnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccn3ccnc3c2)no1
Temperature: 80 °C
Yield: 25.4 %

Procedure:
To a solution of 1-Imidazo[1,2-a]pyridin-7-yl-but-2-yn-1-one (168 mg, 0.91 mmol) and hydroxylamine hydrochloride (94 mg, 1.37 mmol) in DMF (10 ml) was added triethylamine (0.21 ml, 1.83 mmol). The reaction mixture was heated at 80° C. for 18 h, then partitioned between EtOAc and H2O. The organic fraction was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was purified by silica column chromatography (0-50% MeOH in Et2O) to afford the product (46 mg). MS: [M+H]+=200.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[F:14][C:15]1[C:20](B(O)O)=[CH:19][CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][C:15]1[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[Si](C)(C)C#Cc1cccc(-c2cccnc2F)c1
Yield: 92.8 %

Procedure:
To a solution of [(3-bromophenyl)ethynyl](trimethyl)silane (2.28 g, 9.0 mmol) in DME (150 mL) is added (2-fluoropyridin-3-yl)boronic acid (1.41 g, 10.0 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.5 mmol) and a solution of sodium carbonate (3.8 g, 36.0 mmol) in H2O (15 mL) at room temperature. After refluxing for 3 h, the reaction mixture is cooled, quenched with saturated sodium carbonate, diluted with EtOAc. The two layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are washed with brine, dried (MgSO4) and concentrated. The crude mixture is purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give the 2-fluoro-3-{3-[(trimethylsilyl)ethynyl]phenyl}pyridine (2.25 g, 91%) as an oil. MS(+) APPI: 270 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[NH2:12])=[O:6])[CH2:2][CH3:3].[C:13](OC)(OC)([O:18][CH3:19])[CH2:14][CH2:15][CH2:16][CH3:17]>CO>[CH2:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][S:9][C:8]=1[N:12]=[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])[O:18][CH3:19])=[O:6])[CH2:2][CH3:3]
Reactant: CCCCC(OC)(OC)OC
Reactant: CCCNC(=O)c1ccsc1N
Solvent: CO
Product: CCCCC(=Nc1sccc1C(=O)NCCC)OC
Temperature: 130 °C

Procedure:
In a destillation apparatus, a mixture of 1.84 g of 2-aminothiophene-3-carboxylic-acid propylamide and 2.43 g of trimethyl orthovalerate is heated for 2 hours at 130° C. Methanol, which arises during the reaction is directly distilled out of the reaction flask. After cooling, the crude product is purified by column chromatography (eluant:hexane/ethylacetate=1:2). Yield:1.9 g pure 2-(1-n-butyl-1-methoxymethyleneamino)thiophene-3-carboxylic-acid propylamide; m.p. 68-70° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: OCCCCCCBr
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
A solution of 6-bromohexan-1-ol (3.64 g, 0.020 mol) from step 1 in butanone (80 ml) was added at room temperature to a stirred mixture of 4-bromo-4-′-hydroxybiphenyl (5.00 g, 0.020 mol) and potassium carbonate (5.50 g, 0.040 mol) in butanone (70 ml). The reaction mixture was heated under reflux for 48 h. The potassium carbonate was filtered off and the solvent was removed in vacuo, the residue was dissolved in diethyl ether (250 ml) and washed with water (2×150 ml) and dried (MgSO4). The solvent was removed in vacuo and the crude solid was then recrystallised from ethanol to give white crystals.
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[C:14]2[CH:15]=[C:16]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])[CH:17]=[CH:18][C:13]=2[S:12][N:11]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>C(Cl)Cl.CO>[CH3:30][N:21]1[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][C:24](=[O:25])[N:19]([C:16]2[CH:17]=[CH:18][C:13]3[S:12][N:11]=[C:10]([CH2:9][P:4](=[O:3])([OH:5])[OH:8])[C:14]=3[CH:15]=2)[C:20]1=[O:31]
Reactant: CCOP(=O)(Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CP(=O)(O)O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.5 %

Procedure:
A solution of diethyl{{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazol-3-yl}methyl}phosphonate (1.00 g, 0.00210 mol) and bromotrimethylsilane (2.20 mL, 0.0168 mol) in methylene chloride (5.0 mL) is stirred at room temperature overnight and concentrated in vacuo to obtain a residue. The residue is diluted with methanol (10.0 mL), stirred at room temperature for 3.5 hours and concentrated in vacuo to obtain a tan solid. The solid is triturated in boiling methylene chloride, filtered and dried to give the title product as a beige solid (0.650 g, mp >230° C.).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:17]=1[C:18]([NH:12][CH2:11][CH:10]([O:13][CH3:14])[O:9][CH3:8])=[O:19]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CNC(=O)c1cc([N+](=O)[O-])ccc1Cl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
Thionyl chloride (14 mL, 192 mmol) was added-dropwise to a solution of 2-chloro-5-nitrobenzoic acid (10 g, 49.6 mmol) in chloroform (150 mL) at 0° C. The mixture was heated to reflux for 4 h then cooled to r.t., concentrated in vacuo and dried under high vacuum to yield 2-chloro-5-nitrobenzoyl chloride (10 g, 91.7%) as a solid. Under nitrogen, triethylamine (19 mL, 136 mmol) was added slowly to a solution of aminoacetaldehyde dimethyl acetal (5.43 mL, 50.0 mmol) in dry DCM (20 mL) at 0° C. 2-Chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) was slurried in dry DCM (30 mL) and added over a period of 30 minutes. The mixture was allowed to warm to r.t. and stirred overnight then partitioned between water and DCM. The organic phase was washed with saturated sodium bicarbonate solution, water and brine then dried over sodium sulfate and concentrated. The crude product was triturated with petroleum ether then diethyl ether and finally purified by column chromatography on silica gel (60-120 mesh) eluting with ethyl acetate/petroleum ether (2% to 40% gradient) to afford 2-chloro-N-(2,2-dimethoxy-ethyl)-5-nitro benzamide (8.3 g, 63%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Yield: 74 %

Procedure:
Sodium p-hydroxybenzoate (64 g) and 51 g of benzyl chloride were added to 150 g of dimethylformamide, and reacted at 100° C. for 3 hours. Benzyl p-hydroxybenzoate was obtained in a yield of 74%. The ratio of benzyl p-benzyloxybenzoate, a by-product, formed was 10%.
Reaction SMILES: ClC1C=CC([CH:6](OC2CNC2)[C:7]2[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=2)=CC=1.[N-]=[C:22]=O.Cl[C:25]1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:26]=1[CH:27]([O:35][CH:36]1[CH2:39][N:38]([C:40]([NH:42]C(C)(C)C)=[O:41])[CH2:37]1)[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1>>[Cl:51][C:49]1[CH:50]=[CH:25][C:26]([CH:27]([O:35][CH:36]2[CH2:39][N:38]([C:40]([NH:42][CH2:22][C:10]3[CH:9]=[CH:8][C:7]([CH3:6])=[CH:12][CH:11]=3)=[O:41])[CH2:37]2)[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:47][CH:48]=1
Reactant: [N-]=C=O
Reactant: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(Cl)cc2Cl)C1
Reactant: Clc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)cc1
Product: Cc1ccc(CNC(=O)N2CC(OC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)cc1

Procedure:
This material was prepared from 3-(4,4′-dichlorobenzhydryloxy)azetidine (36) and the corresponding commercially available isocyanate, using the procedure described for compound (5)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].Br[CH2:19][C:20]#[CH:21].C1COCC1>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:15]([CH2:21][C:20]#[CH:19])(=[O:17])=[O:16])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C#CCBr
Reactant: CC(=O)Nc1ccc2cc(S(=O)O)ccc2c1
Solvent: C1CCOC1
Solvent: O
Product: C#CCS(=O)(=O)c1ccc2cc(NC(C)=O)ccc2c1
Yield: 90.5 %

Procedure:
160 g (0.64 mol) of 2-acetylaminonaphthalene-6-sulfinic acid were dissolved in 1000 ml of water at pH 6 and the solution was added dropwise to a solution of 84.1 g (0.7 mol) of 3-bromoprop-1-yne and 85 ml of THF. After the addition was complete, the reaction mixture was heated at from 40° to 60° C. until the reaction had ended (check by TLC). The precipitate formed was filtered off with suction at about 10° C., washed with water and dried, leaving 166.4 g of 2-acetylamino-6-(prop-1-yn-3-ylsulfonyl)naphthalene of the formula ##STR24## having a melting point of from 230° to 238° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([Cu])#[N:13]>N1C=CC=CC=1.CCOC(C)=O>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:12]#[N:13])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: N#Cc1cnc2ccccc2c1
Temperature: 250 °C

Procedure:
A suspension of 3-bromoquinoline (1-Im-10, 1.5 g) and CuCN (3 eq) in 10 mL of pyridine in a 25 mL microwave tube was heated at 250° C. for 30 min in a microwave. This was repeated 10 times and the reactions were combined and diluted with 200 mL of EtOAc. The solids were removed by filtration and the EtOAc solution concentrated. The residue was taken up in a solution prepared from 80 mL of 30% aqueous NH3 and 800 mL of water. This was extracted with EtOAc (4×800 mL) then the combined extracts were dried with anhydrous Na2SO4, concentrated and purified by silica gel chromatography (PE:EtOAc=3:1) to give quinoline-3-carbonitrile (2-Im-10).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].[O:17]1[C:19]2([CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[CH2:18]1>CN(C)C=O.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:18][C:19]2([OH:17])[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: C1CC2(CCS1)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC2(O)CCSCC2)cc(C)c1Br
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (700 mg) in N,N-dimethylformamide (7 mL) is added Cs2CO3 (1.7 g) and 1-oxa-6-thiaspiro[2.5]octane (586 mg). The mixture is stirred for 12 hour at 100° C. The mixture is diluted with water and extracted twice with ethyl acetate. The combined organic phases are washed with water and brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→60:40) to give the title compound. Yield: 986 mg; LC (method 7): tR=1.14 min; Mass spectrum (ESI+): m/z=348 [M+NH4]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[OH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1CO.Cl[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[OH:2][CH2:1][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:16]=[CH:15][CH2:14][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:6]=1
Reactant: ClCC=Cc1ccccc1
Reactant: C[O-]
Reactant: OCc1ccccc1O
Agent: [Na+]
Solvent: CO
Product: OCc1ccccc1C=CCOc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
154.3 g (0.8 mol) of 28% sodium methoxide solution in methanol was added to a solution which had been obtained by adding 200 ml of methanol to 99.3 g (0.8 mol) of o-hydroxybenzyl alcohol. The resulting mixture was stirred at a temperature of 40° C. for about 1 hour. 122 g (0.8 mol) of chloromethylstyrene from which polymerization inhibitor had been removed by alkali washing was added dropwise to the mixture. The mixture was stirred under reflux for about 4 hours. The material thus refluxed was allowed to cool to room temperature. The resulting NaCl was filtered out. After the methanol was removed from the filtrate by distillation, the residue was repeatedly and thoroughly washed with hexane until chloromethylstyrene, as raw material, and by-products were completely removed therefrom. 400 ml of chloroform was added thereto for dissolution. The resulting solution was washed with distilled water two or three times. The resulting chloroform phase was separated out. The chloroform phase thus separated was dried by sodium sulfate. The chloroform was then removed by distillation to obtain 123 g of a pale yellow liquid (yield: 64%). This liquid was the desired material. It was confirmed by thin layer chromatography (TLC) using silica gel and gas chromatography (GLC) that this product had a high purity (98% or more).