Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([C:18]3[N:19]=[CH:20][C:21]4[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:22]=4[N:23]=3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C.CN(C=O)C>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:30]([CH3:31])=[CH:29][C:14]2[N:15]=[C:16]([C:18]3[N:19]=[CH:20][C:21]4[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:22]=4[N:23]=3)[S:17][C:13]=2[C:12]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ncc4c(n3)c(C)nn4C)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3ncc4c(n3)c(C)nn4C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
A solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (38 mg, 0.07 mmol) and 5M sodium hydroxide (0.28 mL, 1.4 mmol) in THF (2 mL) and MeOH (0.5 mL) was stirred at 50° C. for 2 h. Reaction mixture was cooled to rt, acetic acid (88 μL) and DMF (0.3 mL) were added and reaction mixture was concentrated to ˜0.3 mL, filtered, purified by Gilson HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) and lyophilized to give desired product. LCMS-ESI+: calc'd for C27H27ClN5O3S: 536.1 (M+H+); Found: 536.2 (M+H+); 1H NMR (400 MHz, CD3OD) δ 9.29 (s, 1H), 7.92 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.62 (br s, 3H), 5.28 (s, 1H), 4.13 (s, 3H), 2.63 (s, 6H), 0.98 (s, 9H).
Reaction SMILES: [F-:1].[K+].O[CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:22].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[F:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:22]
Reactant: [F-]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
First, 1.2 of KF and then 2.9 g. of 3-hydroxy-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one are added to a mixture of 35 g. of HF and 15 ml. of pyridine and the mixture is stirred for 1 hour more. Working up in the customary manner using sodium carbonate solution/ethyl acetate gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([NH:21]C(=O)C)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([NH2:21])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1[nH]nc(-c2cccc(F)c2)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1[nH]nc(-c2cccc(F)c2)c1C#Cc1ccccc1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
A mixture of N-[3-(3-fluorophenyl)-4-(2-phenylethynyl)-1H-pyrazol-5-yl]acetamide (2 g, 6.2 mmol), ethanol (22 mL) and 25% aq. NaOH solution (22 mL) was stirred and heated to 80° C. for 1 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo, to provide the title compound as a solid (1.2 g).
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18]CC.C(O)(=O)CCCCCCC/C=C\CC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:36]([OH:38])=[O:37])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][P:32]([OH:35])([OH:34])=[O:33])=[CH:27][CH:26]=1)(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O
Agent: CCC=CCC=CC/C=C\CCCCCCCC(=O)O
Product: CCC=CCC=CC/C=C\CCCCCCCC(=O)N[C@@H](Cc1ccc(OP(=O)(O)O)cc1)C(=O)O

Procedure:
This compound was prepared as described above for (8), using 0.5 mmol (139 mg) of cis-9,12,15-octadecatrienoic acid; yield 52 mg (20%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0,9-1.0 (t, 3H, ω-CH3); 1.3(s, 8H, 4CH2); 1.4-1.5(br s, 2H, CH2CH2CO); 2.0-2.2 (m, 6H, CH2CO and 2CH2CH═CH); 2.7-2.9 (br s, 4H, 2HC═CH—CH2—CH═CH ); 2.9-3.1 (m, 2H, CH2Ar); 4.3-4.4 (m, 1H, NHCHCO); 5.2-5.4 (br s, 6H, 3HC═CH); 7.0 (s, 4H, Ar); 8.2-8.4 (m, 3H, NH and 2POH).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:18])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH2:13][CH2:14][NH:15][CH2:16][CH:17]=3)[N:7]=2)[CH2:3][CH2:2]1.[F:19][C:20]([F:35])([F:34])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=O.C(N(CC)CC)C.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH:1]1([NH:4][C:5]([C:6]2[N:7]=[C:8]([C:12]3[CH2:13][CH2:14][N:15]([CH:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:27][CH:28]=4)[C:20]([F:35])([F:34])[F:19])[CH2:16][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C(F)(F)F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1cccc(C2=CCN(C(c3ccc(OC(F)(F)F)cc3)C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
Titanium (IV) chloride (0.098 ml, 0.887 mmol) was added to a solution of N-cyclopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide free base (5b) (432 mg, 1.77 mmol), 2,2,2-trifluoro-1-(4-trifluoromethoxyphenyl)ethanone (63) (458 mg, 1.77 mmol) and triethylamine (0.492 ml, 3.55 mmol) in CH2Cl2 (12 ml) and stirred at room temperature for 18 hours. Sodium cyanoborohydride (334 mg, 5.32 mmol) in methanol (4 ml) was added to the reaction mixture and stirred for 19 hours. The reaction was quenched with aqueous NaOH solution (2 N), extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexane: 67/33) to give 1′-[2,2,2-trifluoro-1-(4-trifluoromethoxyphenyl)ethyl]-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (64) (226 mg, yield 26%) as a pale orange oil. 1H NMR (400 MHz, CDCl1): S 8.04 (m, 1H), 8.00 (brs, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.47 (m, 3H), 7.26 (m, 2H), 6.58 (m, 1H), 4.21 (q, J=7.9 Hz, 1H), 3.45 (m, 2H), 2.97 (m, 1H), 2.90 (m, 1H), 2.80 (m, 1H), 2.66 (m, 2H), 0.88 (m, 2H), 0.65 (m, 2H); MS: 486 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:12]([F:13])([F:14])[F:15])(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCC(F)(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCC(F)(F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
1.0 g of 9,9,10,10,10-pentafluorodecan-1-ol is dissolved in 8 ml of abs. pyridine, 985 mg of p-toluenesulphonyl chloride are added at 0° C. and the mixture is stirred in the cold for 2 hours. The reaction mixture is then added to water, extracted 3 times with ether, dried over magnesium sulphate and concentrated in vacuo. Preparative column chromatography on silica gel using a hexane-ethyl acetate gradient leads to 1.5 g of 9,9,10,10,10-penta-fluorodecyl tosylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.[H-].[Na+].CI.[C:18]([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH:6][CH3:18])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)cc([N+](=O)[O-])c1N
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1c(OC)cc(Cl)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To the title compound of Example 21, Step B (19.9 mmol, 4.03 g) in DMF (50 mL) at 0° C. was added portionwise NaH (31.8 mmol, 1.27 g of 60% suspension in mineral oil) (exothermic, gas evolution). After 10 min MeI (23 mmol, 1.5 mL) was added and the reaction was allowed to stand at ambient temperature for 3 h. Saturated NaHCO3 and brine were added to the reaction resulting in formation of a precipitate, which was filtered, washed with water and dried in vacuo. Flash chromatography on silica eluting with 15% EtOAc in hexanes afforded the product as a bright red solid. LC-MS (ESI, Method B): 2.31 min, m/z 217.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][O:16][C:17]([CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:18].O>ClCCl>[CH3:15][O:16][C:17](=[O:18])[CH2:19][CH2:20][C:21]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: Nc1cccnc1
Reactant: COC(=O)CCC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)Nc1cccnc1
Temperature: 0 °C

Procedure:
To a solution of 3-aminopyridine (1 g) in dichloromethane (10 ml) was added triethylamine (1.63 ml) and 3-methoxycarbonylpropionyl chloride (1.44 ml) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was poured into water and extracted with dichloromethane. The extract was washed with water, saturated aqueous NaHCO3 solution, water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1), and recrystallized from diethyl ether to give N-(3-pyridyl)succinamic acid methyl ester (0.73 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I:10]N1C(=O)CCC1=O>CC(O)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:10]
Reactant: O=C1CCC(=O)N1I
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=Cc1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (2.0 g, 16.39 mmol) in AcOH (30 mL) was added N-iodosuccinimide (4.5 g, 19.67 mmol). The reaction mixture was stirred at r.t. for 16 h, then filtered. The filtrate was poured onto water (100 mL) and EtOAc (50 mL) was added. The aqueous fraction was separated, then extracted with EtOAc (3×50 mL). The combined organic fractions were washed with water (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (2.0 g, 50%) as a white solid that was used without further purification. LCMS (ES−) 247.1 (M−H)−, RT 1.44 minutes (Method 9).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 93.8 %

Procedure:
A solution of methyl 4-methylthio-3-nitrobenzoate (11.7 g) and sodium hydroxide (4.1 g) in ethanol (234 ml) and water (117 ml) was heated at reflux for 2 hours and was then concentrated in vacuo to about 70 ml. Water (250 ml) was added and the mixture was warmed to give a solution which was acidified with acetic acid (30 ml). The mixture was stirred while cooling and the resulting solid collected and washed with water to yield 4-methylthio-3-nitrobenzoic acid (10.3 g), m.p. 245°-247° C. [Elemental analysis: C,45.2; H,3.22; N,6.48; S,14.1%; calculated: C,45.07; H,3.29; N,6.57; S,15.02%].
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:14])[N:3]1[CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17].O.[OH-].[Li+].C(=O)([O-])O.[Na+]>C1COCC1.O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:14])[N:3]1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(CN1C(=O)CN(Cc2ccccc2)C1=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CN1C(=O)CN(Cc2ccccc2)C1=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 51.6 %

Procedure:
To a solution of phenylmethyl 2-(2,5-dioxo-3-benzylimidazolidinyl)acetate (3.42 g, 10.0 mmol) in THF—H2O (3:1, 40 ml) was added lithium hydroxide monohydrate (0.85 g, 20.0 mmol). After stirring the mixture at 50° C. for 6 hours, the reaction mixture was alkalized with saturated aqueous sodium hydrogen carbonate solution and washed with ethyl acetate. The aqueous phase was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized with ethyl acetate and filtered off to give 2-(2,5-dioxo-3-benzylimidazolidinyl)acetic acid (1.28 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[N:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26](=[CH:32]N(C)C)[C:27](OCC)=[O:28])[CH:25]=1)#[N:20].Cl.CCN(C(C)C)C(C)C>CC(O)C>[CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:27]([OH:28])=[C:26]([N:24]3[CH:25]=[C:21]([C:19]#[N:20])[CH:22]=[N:23]3)[CH:32]=[N:17]2)=[N:12][CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: N#Cc1cnn(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)c1
Reaction time: 2.5 h
Yield: 39.7 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (103 mg, 0.427 mmol) and ethyl 2-(4-cyano-1H-pyrazol-1-yl)-3-(dimethylamino)acrylate (100 mg, 0.427 mmol) in 2-propanol (1.4 mL) and treated with 1.85N HCl (841 mg, 0.427 mmol). The resulting clear mixture was stirred for 2.5 h and then Hunig's base (297 μl, 1.708 mmol) was added and the resulting red solution was stirred at ambient temperature for 2.5 h. The reaction mixture was then concentrated in vacuo and purified using HPLC (20-95% ACN in water, TFA-buffered). Product-containing fractions were concentrated in vacuo to give a solid (volume ˜50 mL). The solid was filtered and dried in vacuum to give the title compound (65.4 mg, 39.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.53 (d, J=5.81 Hz, 2 H) 7.27 (dq, J=8.46, 4.17 Hz, 1 H) 7.31-7.44 (m, 4 H) 8.29 (s, 1 H) 8.33-8.58 (m, 3 H) 8.93 (s, 1 H) 8.98 (s, 1 H) 9.30 (t, J=5.81 Hz, 1 H) 12.33-14.49 (br s, 1 H). MS m/z [M+H]+ 386.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[O:12]=[C:13]1[CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]2[CH2:32][CH2:31][CH2:30][NH:29]2)=[O:27])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C@@H:28]2[C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][C:13]3=[O:12])=[CH:24][CH:23]=2)=[O:27])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)C1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1CCCN1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 95 mg (0.61 mmol) of 4-chlorophenyl isocyanate are added to a solution of 200 mg (0.61 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]pyrrolidine-2-carboxamide hydrochloride and 1 ml of triethylamine in 5 ml of methylene chloride, and the reaction solution is stirred at room temperature for two hours. The reaction solution is subsequently washed with 5 ml of 1N hydrochloric acid and 5 ml of water, and the methylene chloride solution is dried over sodium sulfate. After the solvent has been stripped off under reduced pressure, the crude product is recrystallised from ethanol/diethyl ether, giving 120 mg of the title compound (“A1”) as a white powder; ESI 443; m.p. 227.6°.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:27][Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].C[Si]([N-][Si](C)(C)C)(C)C.[F:45][C:46]([F:57])([F:56])[CH2:47]OS(C(F)(F)F)(=O)=O.[NH4+].[Cl-]>C1COCC1.CCOCC>[CH2:1]([S:8]([N:11]([CH2:47][C:46]([F:57])([F:56])[F:45])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:27][Si:28]([CH2:31][CH3:32])([CH2:33][CH3:34])[CH2:29][CH3:30])([C:23]([F:24])([F:25])[F:26])[C:19]([F:20])([F:21])[F:22])[CH2:14][CH2:13]1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)Cc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N(CC(F)(F)F)S(=O)(=O)Cc2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Temperature: -40 °C

Procedure:
A solution of 200 mg (0.37 mmol) of trans benzyl-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide (example 29.1) in 2 mL of THF was cooled to −78° C. and treated dropwise with a 0.4 mL of a 1M lithium-bis-(trimethylsilyl)amide-solution in THF. The mixture was warmed to −40° C., treated with 609 mg (2.6 mmol) of trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester and allowed to reach RT. After 4 hours of refluxing, the mixture was cooled to RT and distributed between a saturated aqueous solution of NH4Cl and Et2O. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. Chromatography on silica gel with heptane/EtOAc 9:1 gave 140 mg (61%) of trans benzyl-N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-sulfonamide as a light yellow oil, MS: 614 (M−H)−.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH2:17])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:25](=[O:27])[CH3:26])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c3c(c(F)cc2n1)CCC3=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCC=C1CCc2c(F)cc3nn(C)cc3c21
Reaction time: 0.25 h
Yield: 89 %

Procedure:
2-(5-Fluoro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (78.0 mg, 0.337 mmol) was dissolved in tetrahydrofuran (3.4 mL), triethylamine (56.4 μL, 0.404 mmol) and acetic anhydride (35.0 μL, 0.371 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were washed with diisopropyl ether to give the title compound (82.0 mg, yield 89%).
Reaction SMILES: [Ca:1].[O-:2]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].P(=O)(O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[S:42]([O-:46])([O-:45])(=[O:44])=[O:43].P(O)([O-])([O-])=O.[Ca+2].[S:53]([O-:57])([O-:56])(=[O:55])=[O:54].[Ca+2]>>[OH2:2].[S:42]([O-:46])([O-:45])(=[O:44])=[O:43].[Ca+2:1].[Ca+2:1].[S:53]([O-:57])([O-:56])(=[O:55])=[O:54]
Reactant: O=P([O-])([O-])[O-]
Reactant: [Ca]
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O

Procedure:
This process comprises in a first stage reacting in the presence of excess calcium ions, phosphate rock with at least nine parts by weight of phosphoric acid for each part of calcium added, said phosphoric acid containing at least 37% by weight P2O5 and 1% to 3% by weight dissolved sulfate, whereby the phosphate rock is converted into a slurry comprising monocalcium phosphate, phosphoric acid, and calcium sulfate, the percentage of calcium ion precipitated as calcium sulfate being 10 to 60%, preferably 20-50% by weight of total calcium fed, in a second stage reacting the slurry from the first stage with sulfuric acid whereby phosphoric acid containing at least 40% P2O5 by weight and calcium sulfate hemihydrate is formed, the sulfuric acid being used in an amount 0.5 to 2.0% by weight in excess of that required to convert the calcium content of the phosphate rock fed to the first stage into calcium sulfate. In the third stage, the phosphoric acid is separated from the calcium sulfate and the crystals are washed. The temperature of the first and second stages are in the range from 80° to 111° C., preferably from 90°-110° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:28])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][C:24]([F:27])([F:26])[F:25])[CH:18]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:28])[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23][C:24]([F:27])([F:25])[F:26])[CH:18]=1)[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1cccc(SC(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC1CCCC1)c1cccc(SC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of diisopropylamine (1.5 mL, 10.5 mmol) in dry tetrahydrofuran (27 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (4.2 mL, 10.5 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-trifluoromethylsulfanyl-phenyl)-acetic acid methyl ester (2.50 g, 10.0 mmol) in a small amount of tetrahydrofuran. The reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (2.10 g, 10.0 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (50 mL) and then partitioned between water (75 mL) and ethyl acetate (75 mL). The layers were shaken and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 8/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-trifluoromethylsulfanyl-phenyl)-propionic acid methyl ester (2.95 g, 89%) as a colorless oil: EI-HRMS m/e calcd for C16H19F3O2S (M+) 332.1058, found 332.1047.