Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.C([Li])CCC.[O:21]1CCC[CH2:22]1.C=O>C(OCC)C.CCCCCC>[OH:21][CH2:22][CH2:8][C:6]1[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Reactant: C1CCOC1
Agent: C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(CCO)nc(-n2c(C)ccc2C)c1
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of 2.97 mg (14.8 mmol) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 53, Step A) in 15 mL of ethyl ether was added to a -20° C. solution prepared from 30 mL of ethyl ether and 12 mL (17 mmol) of 1.4 M n-butyllithium in hexane. The mixture was stirred for 1 h at -20 to -15° C. with the formation of a precipitate. Tetrahydrofuran (10 mL) was added, giving an orange-red solution of the intermediate anion. Paraformaldehyde in a separate flask was heated to 150-160° C., generating formaldehyde gas. The formaldehyde, diluted with nitrogen, was introduced as a gas stream impinging on the anion solution (kept at -15 to -10° C.) until the anion color had faded (20-30 min). The mixture was stirred an additional 15 min, quenched by the addition of 50 mL of saturated aqueous ammonium chloride, and extracted with 50 mL of ethyl acetate. The organic layer was washed with 30 mL of saturated aqueous sodium choride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 90 g of silica gel eluting with 2 L of 30% ethyl acetate in hexane to give 1.55 g (45% yield) of 6-(2-hydroxyethyl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as a colorless oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](S(O)(=O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:15]([OH:18])(=[O:17])=[O:16]>O>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([S:15]([OH:18])(=[O:17])=[O:16])[CH:1]=2)[CH:6]=[CH:7][C:8]=1[S:15]([OH:18])(=[O:17])=[O:16]
Reactant: O=S(=O)(O)c1ccc2cc(S(=O)(=O)O)ccc2c1
Solvent: O
Product: O=S(=O)(O)c1ccc2ccc(S(=O)(=O)O)cc2c1
Temperature: 23 °C

Procedure:
To 520 g of the disulfonation reaction mixture obtained in Example 4 was added 180 ml of water to adjust the sulfuric acid concentration to 45% by weight. The mixture was cooled to 23° C. and the precipitated crystal was recovered by filtration to obtain 60 g of 2,7-naphthalenedisulfonic acid having a purity of 97%.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[S:13][C:14]([Cl:15])=[C:10]([Cl:9])[CH:11]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)c(Cl)s2)c1Br
Yield: 42 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 4,5-dichlorothiophene-2-sulphonyl chloride in 42% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 135°-138° C.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:32])[C:16]([CH2:30][CH3:31])=[C:17]([C:28]#[N:29])[C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=O)=[CH:21][CH:20]=1)=[O:13])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(Cl)Cl.O>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:32])[C:16]([CH2:30][CH3:31])=[C:17]([C:28]#[N:29])[C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:27])[NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:23][CH:24]=1)=[O:13])[CH3:10]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)O)cc2)c(C#N)c(CC)n1C
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(=O)Nc3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add N-chlorosuccinimide (0.13 g, 1.0 mmol) to 3-(4-carboxy-phenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.33 g, 11.0 mmol, prepared in example E-157) and triphenyl-phosphine (0.26 g, 1.0 mmol) in methylene chloride at 0° C. with stirring. Allow the reaction to warm to room temperature. After 30 minutes, add aniline (0.18 mL, 2.0 mmol). After 2-3 hours, pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 402.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Fc1ccc(Br)c(I)c1
Product: Fc1ccc(Br)c(Sc2ccc(Cl)cc2)c1

Procedure:
Prepared from 4-chloro-benzenethiol and 1-bromo-4-fluoro-2-iodo-benzene.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]2.[C:21]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:35])[CH3:34])[C:26](O)=O)#[N:22].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:21]([C:23]1[CH:24]=[C:25]([C:26]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]4)[N:20]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH:33]([CH3:34])[CH3:35])#[N:22]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 25 °C
Yield: 50 %

Procedure:
Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (265 mg, 0.96 mmol), 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (197 mg, 0.96 mmol), EDAC (203 mg) and HOBt (142 mg) were stirred in DMF (5 ml) at 80° C. for 2 hours. Stirred at room temperature over the weekend, then heated at 80° C. for a further 4 hours. The reaction mixture was cooled and then partitioned between EtOAc and sodium bicarbonate. The organic layer was separated, washed with brine, dried and evaporated to dryness in vacuo. The crude material was purified by flash chromatography to afford the title compound (214 mg) as a white solid. MS (ES): C24H23N5O4 requires 445; found (MH+) 446.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[C:15]([CH3:22])=[C:16]([CH2:20][OH:21])[CH:17]=[CH:18][CH:19]=1.CCOCC.CCCCCC>ClCCl.C(OCC)C>[CH3:12][O:13][C:14]1[C:15]([CH3:22])=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH:20]=[O:21]
Reactant: COc1cccc(CO)c1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1cccc(C=O)c1C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
A stirred suspension of pyridinium chlorochromate (19.2 g; 89.2 mmol) in dichloromethane at ambient temperature was treated with a solution of (3-methoxy-2-methylphenyl)methanol (9.05 g; 59.47 mmol) in dichloromethane. The reaction solution immediately turned a greenish-brown color. The reaction was stirred for 3.5 hr, diluted 50% with diethyl ether and decanted. The brown gummy residue was triturated twice more with diethyl ether (40 mL) and the ether extracts were combined and evaporated to yield a yellow oil. The oil was passed through a column of silica gel with an ether/hexane mixture to yield the title product, 8.74 g; 97% yield.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4]([OH:6])=O.C(OC(=O)C)(=O)C>>[CH3:1][N:2]1[CH2:3][C:4](=[O:6])[O:10][C:8](=[O:9])[CH2:7]1
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CN1CC(=O)OC(=O)C1
Temperature: 165 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2,2′-(methylazanediyl)diacetic acid (500 mg, 3.40 mmol) and acetic anhydride (5 mL) was stirred at 165° C. for 30 min. The reaction mixture was concentrated under reduced pressure to give 4-methylmorpholine-2,6-dione as a crude product. The obtained crude product was dissolved in THF (10 mL), and p-aminobenzonitrile (401 mg, 3.40 mmol) was added thereto. The mixture was heated with reflux for 22 hr, and concentrated under reduced pressure to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)(methyl)amino)acetic acid (467 mg, 56%) as a pale-brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:8]2=[O:17]
Reactant: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1ccccc1F
Temperature: 25 °C
Yield: 64.9 %

Procedure:
Intermediate 23 (1.1 g, 3.55 mmoles) was taken in a RB flask and to this triethylamine (10 ml) and propionic anhydride (1.44 g, 11.13 mmoles) were added and the mixture was refluxed for 22 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (0.800 g, 65% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.10(d, J=2.5Hz, 1H), 8.00(dd, J=9.0,2.5 Hz, 1H), 7.71(d, J=9.0Hz, 1H), 7.51(m, 1H), 7.36(m, 3H), 2.54(m, 2H), 1.19(t, J=7.6Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]3[O:11][CH:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:13][CH2:14][C:15]=3[C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:8]=2[N:7]=[C:6]1[CH3:28].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]3[O:11][CH:12]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:13][CH2:14][C:15]=3[C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:8]=2[N:7]=[C:6]1[CH3:28]
Reactant: COCCn1c(C)nc2cc(C(=O)OC)c3c(c21)OC(c1ccccc1)CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCn1c(C)nc2cc(C(=O)O)c3c(c21)OC(c1ccccc1)CC3
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A mixture of methyl 1-(2-methoxyethyl)-2-methyl-8-phenyl-1,6,7,8-tetrahydrochromeno[7,8-d]imidazole-5-carboxylate (1.37 g, 3.61 mmol, Step 11), 2 mol/L sodium hydroxide aqueous solution (3.60 mL, 7.21 mmol), and ethanol (20 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature, 2 mol/L hydrochloric acid (3.60 mL, 7.21 mmol) was added, and the formed precipitate was collected by filtration to afford the title compound as a white solid (1.28 g, 96%).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=1
Reactant: O=Cc1ccccn1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Clc1c(NCCNCc2ccccn2)ccc2ccccc12
Yield: 52 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and pyridine-2-carbaldehyde in 52% yield as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:43])[CH:28]([CH:38]1[CH2:42][CH2:41][CH2:40][NH:39]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1>>[CH3:25][O:26][C:27](=[O:43])[CH:28]([CH:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2ccccc2)ccc1C(=O)O
Reactant: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1
Product: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1C(=O)c1ccc(-c2ccccc2)cc1CNC(=O)OC(C)(C)C
Yield: 80 %

Procedure:
3-(tert-Butyloxycarbonylaminomethyl)biphenyl-4-carboxylic acid (1.15 g, 3.5 mmol) and 3-(3-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester (0.91 g, 3.5 mmol) are coupled as described in EXAMPLE 1B to give the title compound (1.22 g, 2.8 mmol). 1H NMR (CDCl3, 300 MHz) □ 7.63-7.25(m, 12H), 4.85-4.70(two m, 1H), 4.48(m, 1H), 4.38(br.s, 2H), 3.80-3.71(m, 1H), 3.68, 3.62(two s, 3H), 3.63-3.40(m, 2H), 3.21-3.10(m, 1H), 2.90-2.78(m, 1H), 2.20-2.05(m, 1H), 2.02-1.65(m, 3H), 1.45(s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:40])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)N5CCOCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 63.5 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and morpholine-4-carbonyl chloride (38 mg, 0.690 mmol) gave 7-cyclopentyl-2-{5-[4-(morpholine-4-carbonyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (80 mg, 62%). MS(ESI) m/z 548.3 (M+H)+
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18].N12CCCN=C1CCCCC2>O1CCOCC1>[C:10]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH:8]=[O:9])[CH2:18][CH2:17][C:16]#[N:19])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: C=CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: N#CCCC(C=O)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of diphenylacetaldehyde (11.0 mL) and acrylonitrile (4.5 mL) in dioxane (125 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (10.5 mL). The solution was heated under reflux overnight and then concentrated in vacuo. The residue was purified by a silica gel column eluting with (95:5) hexane/ethyl acetate. The desired product (8.115 g) was obtained a colorless crystals, mp 80-82° C.: MS showed (M+NH4)+ @ 267; 1H-NMR (CDCl3, δ): 2.05-2.15 (m, 2H), 2.65-2.75 (m, 2H). 7.11-7.45 (m, 10 H), 9.80 (s, 1H); Anal. Calcd for C17HI5NO: C, 81.90; H, 6.60; N, 5.61. Found: C, 81.83; H, 6.64; N, 5.65.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>ClCCCl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH2:14][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: Oc1ccc(Br)cc1CNc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Step 1 Aniline (1.50 mL, 16.42 mmol) was added to a solution of 5-bromo-2-hydroxybenzaldehyde (3.00 g, 14.92 mmol) in 1,2-dichloroethane (100 mL). After 10 min at rt, sodium triacetoxyborohydride (4.74 g, 22.39 mmol) was added. The mixture was stirred at rt. After four days, additional aniline (1.50 mL, 16.42 mmol) and sodium triacetoxyborohydride (4.74 g, 22.39 mmol) were added. After two more days, saturated aqueous ammonium chloride (200 mL) was added. The mixture was stirred at rt for 3 h. The phases were separated and the aqueous phase was extracted with DCM (2×50 mL). The combined organic phases were dried and concentrated. The residue was treated with toluene (25 mL) and hexanes (25 mL) and the mixture was stirred for 30 min. The precipitate was washed with 1:1 mixture of toluene-hexanes (3 mL) and dried under vacuum to give 4-bromo-2-((phenylamino)methyl)phenol as a white solid (2.64 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ 8.70 (1 H, br. s.), 7.18-7.46 (4 H, m), 6.95 (1 H, t, J=7.48 Hz), 6.80-6.90 (2 H, m), 6.77 (1 H, d, J=8.58 Hz), 4.39 (2 H, s), 3.98 (1 H, br. s.). Mass spectrum m/z 278, 280 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:21]COC)=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2].Cl.O>CC(C)=O>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
23 g of (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 230 ml of acetone and 15 ml of concentrated hydrochloric acid was added slowly at room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was gradually poured into 3.5 liters of water. The resultant crystals were filtered, washed with water and dried to obtain 19 g of the titled compound as pale yellow crystals.
Reaction SMILES: C1(C2[O:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:31][C@H:30]([CH2:32][O:33][C:34]6[CH:38]=[CH:37][O:36][N:35]=6)[O:29][C:28]5=[O:39])=[CH:23][C:22]=4[F:40])[CH2:17][CH2:16]3)=[O:14])[CH2:9][O:8]2)C=CC=CC=1>C(O)(=O)C.O>[OH:8][CH2:9][CH:10]([CH2:11][OH:12])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:31][C@H:30]([CH2:32][O:33][C:34]4[CH:38]=[CH:37][O:36][N:35]=4)[O:29][C:28]3=[O:39])=[CH:23][C:22]=2[F:40])[CH2:17][CH2:16]1)=[O:14]
Reactant: O=C(C1COC(c2ccccc2)OC1)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(C(CO)CO)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.2 %

Procedure:
3-(4-(4-(2-Phenyl-1,3-dioxan-5-ylcarbonyl)piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (450 mg, 0.82 mmol) was dissolved in a mixture of acetic acid and water (4:1, 10 ml) and stirred at ambient temperature for 18 hours. After evaporation to dryness, the residue was azeotroped with toluene (15 ml), and the residual gum purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 5 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (237 mg).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][C:16]([O:18]CC)=[O:17])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][C:16]([OH:18])=[O:17])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)N1CCC(COc2ccccc2C(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1OCC1CCN(C(=O)CC(=O)O)C1
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a stirred solution of ethyl 3-{3-[(2-tert-butylphenoxy)methyl]pyrrolidin-1-yl}-3-oxopropanoate (500 mg, 1.44 mmol) obtained in Example 196 in THF (5.0 mL) was added lithium hydroxide (1.0M aqueous solution, 5.0 mL, 5.0 mmol) at room temperature. After 3 hr, the reaction mixture was adjusted to about pH 1 with 1.0N hydrochloric acid. The obtained solution was concentrated under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (451 mg, 98%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[OH-].[Na+].[N:11](OC)=[O:12]>CO>[OH:12][N:11]=[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]#[N:8]
Reactant: CON=O
Reactant: N#CCc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(=NO)c1ccsc1
Temperature: 2.5 °C
Reaction time: 4.5 h
Yield: 39.2 %

Procedure:
In general analogy to the process described under 3.1, 59 g (0.48 mol) of thiophene-3-acetonitril are placed in a sulfonation flask and are charged with 19.2 g (0.48 mol) of sodium hydroxide, dissolved in 200 ml of methanol. 0.48 mol of gaseous methyl nitrite is introduced, with stirring, into this solution at 0-5° C. over 4.5 hours. The ice bath is then removed and the brown solution is stirred overnight at room temperature. The methanol is distilled off on a rotary evaporator and the resulting orange residue is charged with water and ethyl acetate. The aqueous phase is separated, washed twice with ethyl acetate and acidified with conc. HCl. The aqueous phase is extracted twice with ethyl acetate, the extracts are washed with water and dried over magnesium sulfate. After fitration, the solvent is distilled off and a brown solid is obtained which is then recrystallised from toluene, giving 28.6 g (39% of theory) of α-hydroxyiminothiophene-3-acetonitrile as a beige solid having a melting point of 96-106° C. The 1H-NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([OH:12])=[O:11])[CH:8]=1)([O-:3])=[O:2].[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C>[CH3:19][O:11][C:10](=[O:12])[C@H:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC[C@H](C(=O)O)n1cnc([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCC[C@H](C(=O)OC)n1cnc([N+](=O)[O-])c1
Yield: 2813.6 %

Procedure:
(R)-2-(4-Nitro-1H-imidazol-1-yl)-octanoic acid (16.0 g, 63.0 mmol) was dissolved in 1 L of anhydrous methanol. To this solution was added pTsOH (300 mg). The reaction was then heated to reflux for 16 hours. Upon cooling, the solvent was removed in vacuo, to give an oil that was dissolved in 300 mL of ethyl acetate. The solution was washed (2×250 mL) with saturated NaHCO3 solution. The organic was then dried (Na2SO4) and concentrated in vacuo to provide 13.2 g (78%) of (R)-methyl-2-(4-nitro-1H-imidazol-1-yl)-octanoate as an amber oil.