Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]1([C@H:16]([NH:28][C:29]([O:31][C@@H:32]2[CH:37]3[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]3)[CH2:33]2)=[O:30])[C:17]2[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=2)[O:20][CH2:21][C:22](O)=[O:23])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1([C@H](NC(O[C@@H]2C3CCN(CC3)C2)=O)C2C=C(C=CC=2)OCC2C=CC(C(O)=O)=CC=2)C=CC=CC=1>>[N:34]12[CH2:35][CH2:36][CH:37]([CH2:38][CH2:39]1)[C@@H:32]([O:31][C:29](=[O:30])[NH:28][C@H:16]([C:17]1[CH:27]=[CH:26][CH:25]=[C:19]([O:20][CH2:21][C:22]([NH:1][C:2]3[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][OH:6])[CH:3]=3)=[O:23])[CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:33]2
Reactant: Nc1cccc(CO)c1
Reactant: O=C(O)COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Agent: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Product: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1cccc(CO)c1

Procedure:
The title compound was prepared as described in Example 1 Step 11 with 3-aminobenzyl alcohol and 2-(3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)-methyl)phenoxy)acetic acid replacing 3-(1,3-dioxolan-2-yl)propyl piperidine-4-carboxylate hydrochloride and 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)-amino)methyl)phenoxy)methyl)benzoic acid respectively. Crude material used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][P:3](=[S:7])([O:5][CH3:6])[SH:4].[C:8]([O:17][CH2:18][CH3:19])(=[O:16])/[CH:9]=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1(C=CC(O)=CC=1)O>>[CH3:19][CH2:18][O:17][C:8]([CH2:9][CH:10]([S:7][P:3]([O:5][CH3:6])([O:2][CH3:1])=[S:4])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: COP(=S)(S)OC
Agent: Oc1ccc(O)cc1
Product: CCOC(=O)CC(SP(=S)(OC)OC)C(=O)OCC
Temperature: 25 °C

Procedure:
The solution of dimethyl dithiophosphoric acid was added to diethyl maleate (the ratio of dimethyl dithiophosphoric acid to diethyl maleate was approximately 1-1.25 kg: 1.2 kg). Hydroquinone (approximately 3 grams) was added to the mixture. The reaction mixture which contains two separate solutions, an organic solution of diethyl maleate and an aqueous solution of dimethyl dithiophosphoric acid, was mixed for about 8 hours at 53° C. under a nitrogen atmosphere. After mixing, the reaction was cooled to ambient temperature and the organic and aqueous solutions were separated. The organic or diethyl maleate solutions which contained malathion was washed two (2) times with water (approximately 1 liter each time). The organic and aqueous solutions were separated and the malathion in the solution of diethyl maleate retained. This reaction yielded approximately 1.5-1.9 kg of malathion.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[C:5](#[N:7])[CH3:6]>>[NH2:7][C:5]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH3:6]
Reactant: OP(O)O
Reactant: CC#N
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Yield: 75 %

Procedure:
Into a reactor like the above were charged 130.5 g phosphorous acid and 69 g Sulfolane-W (tetramethylene sulfone, Shell Chemical Co.). 31.2 g acetonitrile was introduced slowly for 11/2 hours at 140°-150° C. and the reactants were held for additional 81/2 hours at 153°-158° C. The 1-aminoethane-1, 1-diphosphonic acid produced was isolated from the reaction mixture in the manner described in Example 1. The yield was 75% of the theory on the acetonitrile employed.
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[Cl:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(Cl)cc1OCC2
Reactant: C#CC(C)(O)c1cc(C)on1
Product: Cc1cc(C(C)(O)C#Cc2cc3c(cc2Cl)OCCn2cc(C(N)=O)nc2-3)no1
Yield: 32 %

Procedure:
Similar to as describe in General Procedure G, 10-bromo-9-chloro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with racemic 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol to give the titled compound as a yellow solid (40 mg, 32%).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.O.Cl.[NH2:15][C@@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[C:5]1[CH2:10][CH2:9][C:8]2([S:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[NH:15]2)[CH2:7][CH2:6]1
Reactant: CC(C)CC=C1CCC(=O)CC1
Reactant: N[C@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CC=C1CCC2(CC1)N[C@@H](C(=O)O)CS2
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
In a mixture of 3.5 ml of ethanol and 1.5 ml of water are dissolved 1.0 g of 4-(3-methylbutylidene)-1-cyclohexanone, 1.1 g of D-cysteine hydrochloride monohydrate and 0.52 g of sodium acetate. The resulting solution is stirred at ambient temperature for 2 hours. Water is added to the reaction mixture and the deposited crystal is collected by filtration. Thus, 0.81 g of (3S)-8-(3-methylbutylidene)-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid is obtained as a colorless crystalline product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.Cl[C:12]1[N:17]=[C:16]([NH2:18])[N:15]=[C:14]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:20]=[CH:21][C:13]=12>C1COCC1.[NH4+].[Cl-].[Cl-].[Cl-].[Zn+2].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:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:19]1[C:14]2=[N:15][C:16]([NH2:18])=[N:17][C:12]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[C:13]2[CH:21]=[N:20]1
Reactant: Nc1nc(Cl)c2cnn(Cc3ccccc3F)c2n1
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1nc(-c2nccs2)c2cnn(Cc3ccccc3F)c2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of thiazole (0.14 mL, 2 mmol) in dry THF (10 mL) at −78° C., under argon was treated n-BuLi (1.6-M in hexanes, 1.25 mL, 2 mmol), stirred for 15 min, treated with ZnCl2 solution (1-M in Et2O, 2 mL, 2 mmol) then allowed to warm gradually to room temperature. The mixture was treated with 4-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine (278 mg, 1 mmol) and Pd(PPh3)4 (100 mg, 10 mol %), refluxed for 2 h, diluted with saturated NH4Cl solution, extracted with EtOAc, dried (MgSO4) and concentrated in vacuo. The resulting brown oil was purified by chromatography [SiO2; heptane:EtOAc (4:1) then (3:1)] to give the title compund (101 mg, 31%) as a cream solid.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH2:14])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:1]12([CH2:11][CH2:12][NH2:14])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC(=O)CC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCC12CC3CC(CC(C3)C1)C2
Temperature: 5 °C

Procedure:
In this preparation a mixture containing 15 g. of 1-adamantyl acetic acid and 40 ml. of thionyl chloride is allowed to stand for 16 hours at room temperature. The excess thionyl chloride is then removed by evaporation, under reduced pressure, at 60° C affording adamant-1-yl acetyl chloride as an oil. The oil is then dissolved in 800 ml. of ethyl ether and then ammonia is bubbled through the solution until about 12.8 g. is absorbed. The solution is then washed twice with water, dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording adamant-1-yl acetamide. 12.8 G. of adamant-1-yl acetamide is added to a mixture containing 3 g. of lithium aluminum hydride in 500 ml. of anhydrous tetrahydrofuran at 25°0 C and refluxed for 5 minutes. The mixture is cooled to 5° C, a slight excess of an aqueous saturated solution of sodium sulfate is added dropwise. Thereafter the tetrahydrofuran solution is dried over sodium sulfate, filtered and the solvent evaporated to dryness under vacuum. From the remaining oil, 2-(adamant-1-yl)ethylamine is distilled bulb to bulb, 10.1 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([NH:16][CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[O:22]1[CH2:24][CH:23]1[CH2:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=1>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([N:16]([CH3:17])[CH2:24][CH:23]([OH:22])[CH2:25][O:26][C:27]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(OCC2CO2)cc1
Reactant: CNC1C2CCC1CN(Cc1ccccc1)C2
Agent: C[Al](C)C
Solvent: ClCCl
Product: CN(CC(O)COc1ccc(C#N)cc1)C1C2CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a solution of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (Preparation B; 3.72 g, 16.1 mmol) in dichloromethane (80 mL) at 25° C. under nitrogen was added trimethylaluminum (8.05 mL of 2.0 M in hexane, 16.1 mmol). After stirring at 25° C. for 30 min, 4-(2-oxiranyl-methoxy)benzonitrile (see step (i) above; 2.83 g, 16.1 mmol) was added in one portion, and the mixture was stirred overnight. The mixture was quenched with 6 N NaOH (13.5 mL) and stirred 1 h. Water (100 mL) was added, and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford an oil. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 4.30 g (66%) of the sub-title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=[O:18])=[C:4]2[CH2:3]1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Reactant: CC(C)(C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of 2.6 g (10 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 20 ml of pyridine is firstly treated with 25 ml of t-butanol and subsequently treated dropwise at -5° with 1.1 ml of phosphorus oxychloride. The mixture is stirred at -5° for 15 minutes and at room temperature for 48 hours, poured into 250 ml of water and extracted four times with chloroform. The chloroform extracts are washed three times with dilute sodium hydroxide and three times with water, dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there is obtained t-butyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 216°-217°.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].[ClH:32]>C(O)C.O.CO.C(OCC)(=O)C>[ClH:32].[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH2:13][CH2:12][N:9]3[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCN(CCCN2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
The above ester (1.01 g, 2.57 mmol) was dissolved in ethanol (10 ml), and a solution of sodium hydroxide (0.59 g, 14.8 mmol) in water (1.5 ml) was added. The resulting mixture was stirred at room temperature for 3.5 h. A mixture of water (20 ml) and concentrated hydrochloric acid (3.0 ml) was added, and the aqueous phase was extracted with dichloromethane (3×15 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO4). Evaporation of the solvent gave a foam, which was redissolved in a mixture of methanol (1.0 ml) and ethyl acetate (5.0 ml). Concentration in vacuo afforded a solid, which was suspended in ethyl acetate (15 ml), heated at reflux temperature for 1 minute and allowed to cool to room temperature. The solid was filtered off and dried to give 0.9 g (88%) of the title compound as a powder.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#[N:16].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][NH2:16])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cc(-c2ccccc2)co1
Agent: [Na+]
Solvent: CO
Product: NCc1cc(-c2ccccc2)co1
Reaction time: 12 h
Yield: 21.8 %

Procedure:
Prepare a solution of 4-phenyl-2-formylfuran (1.5 g, 8.7 mmol) and MeOH (35 mL). Add NH4OAc (6.7 g, 87.1 mmol) and NaCNBH3 (380 mg, 6.1 mmol). Stir the reaction mixture under nitrogen for 12 hours. Upon completion of the reaction, concentrate the resulting mixture, dilute with water (10 mL), basify with 1 N sodium hydroxide, and extract with diethyl ether (2×10 mL). Dry the organic phase (Na2SO4), filter, and concentrate. Perform flash chromatography on silica gel eluting with 9:1 ethyl acetate/MeOH to afford the title compound (230 mg) as a white solid. 1H NMR (CDCl3) δ 7.65 (s, 1H), 7.46 (d, J=7 Hz, 1H), 7.36 (t, J=7 Hz, 1H), 7.26 (m, 1H), 6.49 (s, 1H), 3.89 (s, 2H), 2.10 (s, 2H).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]([CH2:24][CH2:25][Cl:26])[C:9]1[CH:14]=[C:13]([C:15]([NH2:17])=[O:16])[C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22])(=O)=O.[Li+].[Br-:28]>CC#N>[Br:28][CH2:6][CH2:7][N:8]([CH2:24][CH2:25][Cl:26])[C:9]1[C:10]([N+:21]([O-:23])=[O:22])=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([CH:14]=1)[C:15]([NH2:17])=[O:16]
Reactant: [Br-]
Reactant: CS(=O)(=O)OCCN(CCCl)c1cc(C(N)=O)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Li+]
Solvent: CC#N
Product: NC(=O)c1cc(N(CCCl)CCBr)c([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
A mixture of 2-[5-(aminocarbonyl)(2-chloroethyl)-2,4-dinitroanilino]ethyl methanesulfonate (5) [Friedlos et al., J. Med. Chem. 1997, 40, 1270] (0.91 g, 2.2 mmol) and LiBr (0.21 g, 2.4 mmol) in anhydrous MeCN (25 mL) was stirred under reflux for 1.5 h, then concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (3:2) to give a crude product contaminated with the corresponding dibromo mustard. Purification by multiple recrystallisations from EtOAc/I—Pr2O gave IIa2 (595 mg, 68%):
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1F.C([Mg]Cl)(C)C.[N+:14]([C:17]1[CH:24]=[CH:23][C:22](C)=[CH:21][C:18]=1[CH:19]=[O:20])([O-:16])=[O:15].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1COCC1>[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[C:19]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])([O-:16])=[O:15]
Reactant: Fc1ccccc1I
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(C)[Mg]Cl
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 84.8 %

Procedure:
2-Iodofluorobenzene (2.0 mL, 17 mmol) was dissolved in anhydrous THF (20 mL) under an argon atmosphere and cooled to −20° C. A solution of isopropyl magnesium chloride (8.5 mL, 17.0 mmol) was slowly added, and the solution was stirred for 20 min. 2-Nitro-5-methylbenzaldehyde (2.7 g, 16.5 mmol) in THF (20 mL) was then added, and the mixture was stirred for 20 min at −20° C. and then quenched with saturated aqueous NH4Cl. The mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic portion was collected, dried over MgSO4, filtered and evaporated in vacuo. This material was dissolved in anhydrous CH2Cl2 (80 mL). Silica gel (20.3 g) and pyridinium chlorochromate (5.4 g, 25 mmol) were then added and the suspension was stirred at room temperature for 3 h. The mixture was then filtered through silica gel. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, hexanes:EtOAc, 3:2) to provide the 2-nitro-benzophenone (3.7 g, 14 mmol). The benzophenone was dissolved in glacial acetic acid (50 mL), MeOH (50 mL) and deionized H2O (10 mL). Iron powder (<10 micron, 1.0 g) was added with vigorous stirring and the suspension heated to 60° C. After 20 min, additional iron powder (2.0 g) was added and the mixture was stirred at 60° C. for 3 h. After cooling, silica gel (12.5 g) was added and the volatile components were removed in vacuo. The resulting powder was suspended in EtOAc (100 mL) and carefully treated with 1N NaOH until basic to litmus. The suspension was filtered and the organic portion was separated, washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, hexanes:EtOAc, 1:3) to provide 1af (3.1 g, 94%) MS m/z=230 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]([CH3:39])[C:35]([F:37])([F:38])[F:36])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(C)C(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC(C)C(F)(F)F)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
48 mg (0.08 mmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-5,5,5-trifluoro-4-methylpentanoyl}amino)benzoate (mixture of racemic diastereomers) were hydrolysed with TFA according to General Method 2. Yield: 24 mg (56% of theory)
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].[Sb](Cl)(Cl)[Cl:15].II.P(Cl)(Cl)Cl.ClCl>>[Cl:15][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[CH:3]([CH2:2][Cl:1])[CH3:4]
Reactant: Cl[Sb](Cl)Cl
Reactant: CC(CCl)c1ccc([N+](=O)[O-])cc1
Agent: ClCl
Agent: II
Solvent: ClP(Cl)Cl
Product: CC(CCl)c1ccc([N+](=O)[O-])cc1Cl
Temperature: 25 °C

Procedure:
24 g (0.12 Mol) of 4(1-chloromethyl-ethyl)-nitrobenzene, 1 g of antimony trichloride, 50 mg of iodine and 16 mg of PCl3 are gradually warmed to 60°. Through the resulting homogeneous syrup a current of dry chlorine is passed at such a rate that the temperature inside the flask does not rise above 70°. When little more than the theoretical amount of chlorine is absorbed (5.3 g/20 minutes) the brown reaction mixture is cooled to ambient temperature and then taken up in 125 ml of toluene. The toluene solution is washed with five 150 ml portions of water, dried (Na2SO4) and evaporaed in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([CH:8]=1)[NH2:7].[S:14]1[C:18]([C:19](Cl)=[O:20])=[CH:17][C:16]2[CH:22]=[CH:23][CH:24]=[CH:25][C:15]1=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[C:6]([NH:7][C:19]([C:18]2[S:14][C:15]3[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=3[CH:17]=2)=[O:20])[CH:8]=1
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: Nc1cc(Cl)ccc1-c1nnn[nH]1
Product: O=C(Nc1cc(Cl)ccc1-c1nnn[nH]1)c1cc2ccccc2s1
Yield: 5 %

Procedure:
The title compound was prepared essentially according to the method of Example 4, but using 5-Chloro-2-(1H-tetrazol-5-yl)aniline (1.0 mmol) and benzo[b]thiophene-2-carbonyl chloride. After precipitation, the product was further purified by recrystallization in ethanol to yield the desired product (19.6 mg, 5%). 1H NMR (400 MHz, d6-DMSO): δ 8.61 (s, 1H), 8.31 (s, 1H), 8.09 (m, 3H), 7.53 (m, 3H). MS (EI) for C16H10ClN5OS: 355.8 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH2:38]O)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:38][CH:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30]3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CCc2ccccc21
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(OCC4CCc5ccccc54)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and indan-1-yl-methanol. MS (ESI) m/z 510.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].[Br:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+]>O>[CH2:1]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:15][CH2:14][CH2:13][Br:12])[CH:2]=[CH2:3]
Reactant: BrCCCBr
Reactant: C=CCc1cc(F)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCc1cc(F)ccc1OCCCBr

Procedure:
To a stirred and refluxing mixture of 162 parts of 2-allyl-4-fluorophenol, 363 parts of 1,3-dibromopropane in 700 parts of water is added dropwise a solution of 56 parts of sodium hydroxide in 175 parts of water. Upon completion, the whole is stirred and refluxed for 8 hours. After cooling, the aqueous layer is separated and extracted with chloroform. The extract is dried over magnesium sulfate, filtered and evaporated. The oily residue is distilled twice, yielding 142 parts of 3-allyl-4-(3-bromopropoxy)fluorobenzene; bp. 160°-170° C. at 14 mm. pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH3:37])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@H:34]([CH3:37])[CH2:35][OH:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: C[C@@H](N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 2) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+] 525.2290, observed 525.2294.