Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:6][N:7]([CH2:11][CH2:12][O:13][CH:14]=[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:9][CH:10]=1)=[O:4].[OH-].[Na+].O.[ClH:31]>C(O)C>[ClH:31].[C:22]1([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][O:13][CH2:12][CH2:11][N:7]2[CH2:8][CH2:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH2:6]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Reaction time: 2.5 h

Procedure:
1-(2-((2,2-Diphenylethenyl)oxy)ethyl)-1,2,5,6-tetrahydro3-pyridinecarboxylic acid methyl ester (4.33 g, 0.0115 mol, prepared similarly to the method described in Example 70) was dissolved in ethanol (50 ml) and 10 N sodium hydroxide solution (11.5 ml) was introduced, followed by water (5 ml). The solution was stirred at room tempeature for 2.5 h and stored at 4° C. for 18 h. 2 N hydrochloric acid solution was added until the pH 2, and the mixture was extracted with dichloromethane (3×60 ml). The combined extracts was dried (MgSO4) and evaporated to give a foam (4.24 g) which was crystallized from 2-propanol to provide the compound (2.32 g, 52%) as a white solid.
Reaction SMILES: [ClH:1].CO[C:4](=[O:32])[CH:5]([NH:18][S:19]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=[O:21])=[O:20])[CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([NH2:17])=[N:12][CH:11]=[CH:10]2.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[ClH:1].[NH2:17][C:13]1[C:14]2[C:9](=[CH:8][C:7]([CH2:6][CH:5]([NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[C:4]([N:37]3[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]3)=[O:32])=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CC1CCNCC1
Agent: Cl
Product: CC1CCN(C(=O)C(Cc2ccc3c(N)nccc3c2)NS(=O)(=O)c2ccc3ccccc3c2)CC1

Procedure:
Compound 11a was saponified and subsequently coupled with 4-methylpiperidine using the procedure described for 4 to give 11b. 1H-NMR 200 MHz (CD3OD) δ: 0.15-3.24 (12H, m), 3.75-4.24 (2H, m), 4.57-4.72 (1H, m), 6.71-7.91 (10H, m), 8.11-8.19 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[N:35]1[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[NH:1][C:41]([C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[O:42])[C:6](=[CH2:11])[C:7]([O:9][CH3:10])=[O:8])(=[O:14])=[O:15])=[CH:17][CH:18]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: O=C(Cl)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C(=O)OC)N(Cc1ccccc1NC(=O)c1ccncc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 3.0 ml (21.6 mmol) of triethylamine in 15 ml of CH2Cl2 cooled to 0° C. was added 1.7 g (9.5 mmol) ml of 4-pyridinecarbonyl chloride (isonicotinoyl chloride). The mixture was stirred at room temperature overnight and diluted with CH2Cl2. The mixture was washed with H2O, 2 N citric acid, and brine and then dried with Na2SO4. The solvent was removed to give 1.8 g of a light tan solid; Anal. for C24H23N3O6S: Calc'd: C,59.9; H,4.8; N,8.7; S,6.6; Found: C,59.0; H,4.8; N,8.5; S,6.9; Mass spectrum (ES) 482.6(M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13](Cl)=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:22])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:14][C:15]=3[Cl:19])[NH:10][C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(N)cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc(Cl)c3c(c2)NC(=O)C(C)(c2ccc(N)cc2)C3=O)CC1
Yield: 72.7 %

Procedure:
A mixture of 3-(4-amino-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.1 g, 0.30 mmol) and 1-methylpiperazine (36 mL, 0.36 mmol) in dry pyridine (5.0 mL) was heated at reflux temperature overnight. After evaporation of the solvent in vacuo, the residue was diluted with water (50 mL), and resulting suspension was extracted with ethyl acetate (50 mL×3). The organic layer was washed with brine (50 mL×2) and dried over anhydrous MgSO4 concentrated under reduced pressure. The pure objective compound (87 mg, 73%) was obtained as yellow solid by a flash column chromatography (CH2Cl2:MeOH=20:1): 1H NMR (200 MHz, CDCl3) δ 1.78 (s, 3H, CH3) 2.35 (s, 3H, NCH3), 2.43-2.67 (m, 4H, NCH2), 2.90-2.95 (m, 4H, NCH2), 3.67 (br s, 2H, NH2), 6.38 (d, J=1.8 Hz, 1H, ArH), 6.54-6.61 (m, 3H, ArH), 7.04 (d, J=8.6 Hz, 2H, ArH), 8.44 (br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]([CH:22]2[CH2:24][CH2:23]2)[CH3:21])[C:14]=1[NH2:25].[C:26](OCC)(=[O:30])[C:27]([CH3:29])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[C:13]1[C:14]2[N:25]=[C:27]([CH3:29])[C:26](=[O:30])[N:19]([CH:20]([CH:22]3[CH2:24][CH2:23]3)[CH3:21])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: CCOC(=O)C(C)=O
Reactant: CC(Nc1ncnc(-c2ccc(OC(F)(F)F)cc2Cl)c1N)C1CC1
Solvent: CCO
Product: Cc1nc2c(-c3ccc(OC(F)(F)F)cc3Cl)ncnc2n(C(C)C2CC2)c1=O
Reaction time: 18 h

Procedure:
6-(2-Chloro-4-trifluoromethoxy-phenyl)-N4-(1-cyclopropyl-ethyl)-pyrimidine-4,5-diamine (0.20 g, 0.52 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.58 ml, 5.2 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 4.5 mg of 4-(2-chloro-4-trifluoromethoxy-phenyl)-8-(1-cyclopropyl-ethyl)-6-methyl-8H-pteridin-7-one (Example 1062). 1H NMR (300 MHz, CDCl3) δ ppm 8.99 (s, 1 H), 7.50 (d, J=8.79 Hz, 1 H), 7.39 (d, J=1.10 Hz, 1 H), 7.26 (dd, J=8.79, 1.10 Hz, 1 H), 4.91 (m, 1 H), 2.49 (s, 3 H), 1.71 (d, J=7.32, 3 H), 0.69 (m, 2 H), 0.41 (m, 2 H), 0.22 (m, 1 H). MS (EI) 425.2 [(M+H)+, 100].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=O)[NH:15][C:13]1=[O:14].B(O)(O)O>C(O)(=O)C>[CH:3]1[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[C:5]2[N:9]=[C:16]3[NH:15][C:13](=[O:14])[NH:12][C:20](=[O:21])[C:18]3=[N:10][C:4]=12
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: OB(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2nc3cc(Cl)c(Cl)cc3nc2[nH]1
Yield: 99.9 %

Procedure:
A solution of 10 g of 4,5-dichloro-o-phenylenediamine, 9 g of alloxan hydrate, 1.5 g of boric acid and 250 ml of glacial acetic acid was stirred overnight at room temperature to obtain a brown-black solution which was filtered. The yellow-buff crystalline solid was well washed with water to obtain 15.9 g of 7,8-dichloro-alloxazine melting at >370° C. A solution of 2 g of 7,8-dichloro-alloxazine in 10 ml of concentrated sulfuric acid was slowly heated to 240° C. and held there for 10 minutes. The mixture was cooled and poured onto ice and the mixture was made alkaline with sodium hydroxide addition. The mixture was extracted several times with ether to obtain 0.73 g of 2-amino-6,7-dichloro-quinoxaline as an orange crystalline solid melting at 220° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:37]=[CH:36][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])[O:25][C:26]=3[CH3:27])=[C:18]([O:38][CH3:39])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:40](P(=O)(OCC)OCC)[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44].CN(C)C=O.[H-].[Na+]>O>[C:31]([C:30]1[CH:29]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][O:20][C:19]3[CH:36]=[CH:37][C:16]([CH2:15][O:14][C:4]4[C:3](/[CH:1]=[CH:40]/[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[CH:7][N:6]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[N:5]=4)=[CH:17][C:18]=3[O:38][CH3:39])[N:23]=2)[CH:35]=[CH:34][CH:33]=1)#[N:32]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C#N)c3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of 3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (2.50 g), tetraethyl methylenediphosphonate (1.53 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.23 g) at room temperature. The mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl [(E)-2-{3-[(4-{[2-(3-cyanophenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl]phosphonate as colorless crystals (2.20 g, yield 70%) from a fraction eluted with ethyl acetate-hexane (4:1 to 9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 147-148° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[S:12][C:13]([C:16]3([O:26][CH3:27])[CH2:20][CH2:19][N:18]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:17]3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:29][OH:30]>>[OH:30][N:29]=[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[S:12][C:13]([C:16]3([O:26][CH3:27])[CH2:20][CH2:19][N:18]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:17]3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COC1(c2ccc(Sc3ccc(C(C)=O)cc3)s2)CCN(CC(F)(F)F)C1
Reactant: NO
Agent: Cl
Product: COC1(c2ccc(Sc3ccc(C(C)=NO)cc3)s2)CCN(CC(F)(F)F)C1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[2-(4-acetylphenylthio)thien-5-yl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{2-[4-(1-hydroxyiminoethyl)phenylthio]thien-5-yl}-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 63% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=3)=[CH:15][CH:16]=2)[CH2:6]1)=[O:4]
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(OCc3ccc(F)cc3)cc2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
A solution of 5.0 g (21.3 mmol) of (RS)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester [Example 2 b)] in 200 ml of 2-butanone is treated with 3.55 ml (27.6 mmol) of 4-fluorobenzyl-bromide and 5.88 g (42.5 mmol) of potassium carbonate and the mixture is stirred at 90° C. for 3 hours. For the working-up, the reaction mixture is diluted with ethyl acetate and extracted with water. The organic phase is separated, dried over sodium sulfate and evaporated under reduced pressure. For purification, the material obtained is chromatographed on silica gel using a 98:2-mixture dichloromethane and methanol as the eluent. There are obtained 7.18 g (98% of theory) of (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid. MS: m/e=344 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.[Cu][C:14]#[N:15]>CC(N(C)C)=O>[CH:11]([C:4]1[CH:3]=[C:2]([C:14]#[N:15])[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=1)=[O:12]
Reactant: N#C[Cu]
Reactant: O=Cc1cc(Br)c2c(c1)CCO2
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(C=O)cc2c1OCC2
Yield: 61.4 %

Procedure:
To a solution of 7-bromo-2,3-dihydro-1-benzofuran-5-carbaldehyde (1.3 g, 4.7 mmol) in dimethylacetamide (2 mL) was added copper(I) cyanide (0.41 g g, 4.7 mmol). The reaction was refluxed for 18 hours, and then concentrated under reduced pressure. The residue was washed well with warm ethyl acetate. The combined ethyl acetate layer were concentrated and dried. The crude product was purified by flash column chromatography (silica gel, 4:1 and 2:1 hexane:ethyl acetate gradient) to afford the desired product (0.5 g, 50%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Cl.[NH2:16][OH:17]>CC(O)C.O>[Br:1][C:2]1[C:3]([S:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:5]=[N:16][OH:17])[CH:7]=[CH:8][CH:9]=1
Reactant: NO
Reactant: CC(C)(C)Sc1c(Br)cccc1C=O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)Sc1c(Br)cccc1C=NO
Temperature: 67.5 °C

Procedure:
A mixture of 3-bromo-2-tert-butylsulfanyl-benzaldehyde (6.7 g, 25 mmol) and hydroxylamine hydrochloride (7.9 g, 116 mmol) in 2-propanol (200 mL) and water (40 mL) was heated to 65-70° C. overnight. 2-Propanol was evaporated and water (150 mL) was added to the residue followed by saturated aqueous sodium bicarbonate to bring the pH to ˜8.5. The mixture was extracted with DCM (3×80 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to afford the title compound, which was used immediately without further purification. 1H NMR (300 MHz, CD3OD): δ 1.28 (s, 9H), 7.25-7.35 (t, J=7.8 Hz, 1H), 7.79 (d, J=6.6 Hz, 1H), 7.89 (d, J=6.3 Hz, 1H), 8.83 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](=O)([O-:13])N.[BH4-].[Na+]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:13])[CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: NC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cnc2ccccc2c1

Procedure:
Synthesis of compounds ERW1041A, B, C, D, E, and 1069 were synthesized using the methods of Choi et al. Chemistry & Biology, Volume 12, Issue 4, Pages 469-475, except the amino-acid amines are protected by a quinoline-containing carbamate. This quinoline-containing carbamate is synthesized by reducing 3-quinolylcarbaldehyde with sodium borohydride in THF followed by an aqueous workup and flash chromatography yielding 3-quinolylcarbinol. para-Nitro-phenylchloroformate is reacted with 3-quinolylcarbinol in methylene chloride and N-methyl morpholine to give a carbonate of 3-quinoline methanol and para-Nitro-phenol. After purification by flash chromatography, this carbonate is reacted with the methyl ester of the amino acid in neat DMF to give the named compounds.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)(=[O:8])=[O:7]>C(OCC)(=O)C>[CH3:5][S:6]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)(=[O:8])=[O:7]
Reactant: CS(=O)(=O)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylsulfonyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:14][N:15]([CH3:17])[CH3:16])=[CH:5][CH:6]=1)#[N:9]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of 4-acetylbenzonitrile (51.84 g, 0.357 mol) and N,N-dimethylformamide dimethyl acetal (142 ml, 1.07 mol) was heated to reflux for 1.5 h. The reaction was cooled to room temperature and the resultant crystalline mass collected by filtration and washed with diethyl ether (4×100 ml) to give 1-(4-cyanophenyl)-3-dimethylaminopropen-1-one as an orange solid (44.56 g). An additional crop of this product (11.40 g) could be obtained by partially concentrating the filtrate. δH (d6DMSO) 8.01 (2H, d, J 8.2 Hz), 7.87 (2H, d, J 8.2 Hz), 7.75 (1H, d, J 12.2 Hz), 5.83 (1H, d, J 12.2 Hz), 3.15 (3H, bs), 2.92 (3H, bs). MS (ESI) 201 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][C@H:18]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][C@@H:17]12>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:16]2[CH2:20][CH2:19][C@H:18]3[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][C@@H:17]23)[CH:12]=[N:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(OCc4ccccc4)c3)[C@@H]2C1

Procedure:
3-(Benzyloxy)-5-bromopyridine and (3aS,6aS)-tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (prepared as described in WO2001081347) were processed as described in Example 53B to provide the title compound. MS(ESI) m/z 396 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[NH:13]([C:15](=[O:20])[C:16](OC)=[O:17])[NH2:14]>CO>[NH:13]([C:15](=[O:20])[C:16]([NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)=[O:17])[NH2:14]
Reactant: NCc1cccc2ccccc12
Reactant: COC(=O)C(=O)NN
Solvent: CO
Product: NNC(=O)C(=O)NCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.25 ml 1-aminomethylnaphthalene are added to a solution of 1.0 g methyl hydrazino-oxo-acetate in 10 ml of methanol. The solution is stirred for 16 h at ambient temperature and then some of the methanol is eliminated. The precipitate is separated off, washed with diethyl ether, and dried.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10](Cl)[C:11](=[CH2:13])[CH3:12]>>[CH2:12]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]1=[O:9])[C:11](=[CH2:10])[CH3:13]
Reactant: C=C(C)CCl
Reactant: O=C1CCCCCCC1
Product: C=C(C)CC1CCCCCCC1=O

Procedure:
2-Methallylcyclooctanone was prepared starting from cyclooctanone and methallyl chloride, analogously as described in example 1 in the allylation section.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]=12.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1>>[CH:9]([O:8][C:6]1[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:3]2=[C:2]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=2)[CH:7]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1cc(Cl)c2c(n1)CCC2
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc(Nc2cc(OC(C)C)nc3c2CCC3)cc1
Yield: 85.3 %

Procedure:
Following general procedure B1, 4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (0.090 g, 0.43 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.114 g, 0.64 mmol) to afford the title compound (0.130 g, 86%) as a yellow gel. MW=354.44. APCI MS m/z 355 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)C.BrBr.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+].Cl.NO.C([O-])(=O)C.[Na+]>CN(C)C=O.C(O)C.COCCO.CCCCCCC>[C:11]([CH2:10][C:6]1[C:5](=[O:4])[CH2:9][CH2:8][CH:7]=1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC1=C(OC(C)=O)CCC1
Agent: BrBr
Agent: CC(=O)[O-]
Agent: Cl
Solvent: COCCO
Solvent: CCO
Solvent: CCCCCCC
Product: CCOC(=O)CC1=CCCC1=O

Procedure:
In the manner described in Example 28, treatment of 1-acetoxy-2-(carbethoxymethyl)cyclopent-1-ene (Example 21) with bromine and subsequent dehydrobromination with lithium bromide-lithium carbonate in N,N-dimethylformamide gives an amber oil. This material is subjected to chromatography on diatomaceous earth using an n-heptane:methyl cellosolve system. Removal of the solvent from hold back volume 4.5-4.7 gives an oil which is then further treated with hydroxylamine hydrochloride, sodium acetate in ethanol at room temperature for 18 hours to give the desired product; b.p. 71° C. (0.12 mm); λmaxMeOH 222 mμ (10,300); λmax 5.75, 5.85, 6.15, 8.65 μ.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].I[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[O:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:2]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccc(OC)cc1
Product: COc1ccc(-c2cc3ccccc3o2)cc1

Procedure:
The general procedure was used to convert 4-ethynyl-anisole and 2-iodophenol to the title product. Purification by flash chromatography (20% ethyl acetate in hexanes as the eluent) gave the analytically pure product as a white solid (277 mg, 62% yield). 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J=8.48, 2H), 7.54-7.47 (m, 2H), 7.34-7.20 (m, 2H), 6.95 (d, 2H), 6.85 (s, 1H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 159.95, 156.03, 154.68, 129.49, 126.39, 123.72, 123.31, 122.81, 120.55, 114.22, 110.97, 99.65, 55.31 Anal. Calcd. for C15H12O2: C, 80.34; H, 5.39. Found C, 80.34; H, 5.40. m.p.: 149-150° C. (lit., 3146-147° C.).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:18]=[CH:17][C:10]([C:11](N(C)OC)=[O:12])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:19]([Mg]Br)=[CH2:20].Cl>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([CH:19]=[CH2:20])=[O:12])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(C(=O)N(C)OC)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)c1ccc(OCCCCC)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-n-pentyloxybenzoyl)-N,O-dimethylhydroxylamine (4.52 g) in tetrahydrofuran (25 ml) was added 1.6 molar tetrahydrofuran solution of vinylmagnesium bromide (25.5 ml) at −50° C. dropwise and the mixture was stirred for 3 hours at −20° C. To the mixture was added 1N HCl (50 ml) dropwise and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate)=(8/2) to give 1-(4-n-pentyloxyphenyl)acrolein (2.40 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].I[CH2:16][CH:17]([CH3:19])[CH3:18]>CC(C)=O>[CH2:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CI
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)COc1ccccc1Br
Temperature: 25 °C
Yield: 24.8 %

Procedure:
To a solution of 2-bromophenol (0.67 ml, 5.8 mmol) in 25 ml acetone was added K2CO3 (2.0 g, 14.5 mmol) and 1-iodo-2-methylpropane (0.75 ml, 6.4 mmol). The reaction mixture was heated to reflux for 19 h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH×2, water and brine. Drying over Na2 SO4 afforded 330 mg (25%) of 2-isobutoxybromobenzene.