Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4](=[O:14])[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([F:12])=[CH:7][C:6]=1[Cl:13].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>N1C=CC=CC=1>[Cl:13][C:6]1[C:5]([C:4](=[O:14])[N:3]([O:2][CH3:1])[CH3:15])=[CH:10][C:9]([NH:11][C:17](=[O:18])[O:19][CH2:20][CH3:21])=[C:8]([F:12])[CH:7]=1
Reactant: CON(C)C(=O)c1cc(N)c(F)cc1Cl
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(C(=O)N(C)OC)c(Cl)cc1F
Temperature: 0 °C

Procedure:
55.6 g of N-methoxy-N-methyl-5-amino-2-chloro-4-fluorobenzamide are dissolved in 200 ml of pyridine and the solution is cooled to 0° C. 30.4 g of ethyl chloroformate are added dropwise at 0° C. while stirring and thereafter the reaction mixture is stirred for 14 hours. The mixture is poured into 1 liter of ice-water, the aqueous mixture is extracted three times with 250 ml of ethyl acetate each time, the combined organic phases are washed to neutrality, dried over anhydrous sodium sulphate and the solvent is evaporated off. The product is crystallized from diethyl ether. In this manner there is obtained ethyl 4-chloro-2-fluoro-5-(N-methoxy-N-methylcarbamoyl)-carbanilate, m.p. 121° C., used as the starting material in Example 1.
Reaction SMILES: [N:1]1([C:5]2[C:6]3[CH2:28][CH2:27][CH:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=4)[C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[N:10]=2)[CH2:4][CH2:3][CH2:2]1>C(=O)=O.CO>[N:1]1([C:5]2[C:6]3[CH2:28][CH2:27][C@H:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:37])([F:38])[F:39])=[CH:31][CH:30]=4)[C:7]=3[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19]4)=[C:14]([O:24][CH3:25])[CH:13]=3)[N:10]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1cc(Nc2nc3c(c(N4CCC4)n2)CCC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N4CCC4)n2)CC[C@@H]3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of 4-(azetidin-1-yl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (92 mg, 0.165 mmol from Example 101) was purified using chiral SFC to afford 37.6 mg of peak A (Example 101A) and 39.1 mg of peak B (Example 101B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 18 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.7 min, tR (peak B) 13.6 min. The absolute stereochemistry of individual enantiomers (Examples 101A and 101B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 101).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([O:23]CC)=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=[O:22])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
688 mg of the compound of Example 51A with 76% purity (1.23 mmol) are provided in 29 ml of tetrahydrofuran and, at room temperature, 389 mg (16.2 mmol) of lithium hydroxide and 10 ml of water are added. The mixture is stirred at room temperature for 5 h, a 1N aqueous hydrogen chloride solution is subsequently added until the pH is acidic, and the mixture is extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue is stirred in a little cyclohexane and the precipitate is collected by suction filtration. 413 mg (83% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([I:13])[CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)([O-])=O.[OH-].[Na+]>C(O)C>[I:13][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([NH2:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(N)cc(I)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Chart A, Step A-1. To a stirred solution of 3,5-dinitroiodobenzene (6.65 g, 22.6 mmol, starting material in CHART A) in ethanol (94 mL) is added stannous chloride (51.0 g, 226 mmol). The reaction mixture is heated at 70° C. for 1 hour. The reaction mixture is cooled and poured onto ice (300 cc) and the pH is adjusted to 8 with 10% aqueous sodium hydroxide. A thick white precipitate forms and the reaction mixture is filtered through a pad of celite. The filter cake is first washed with ethyl acetate and then stirred with ethyl acetate (300 mL) for 30 min. The celitc mixture is filtered again and filtrates are combined. The phases of the filtrates are separated and the aqueous phase is extracted with ethyl acetate (3×400 mL). The combined organics are dried (Na2SO4), filtered and concentrated. The organic residue is purified by flash chromatography using 50% ethyl acetate in hexane to afford 4.53 g of 5-iodo-1,3-phenylenediamine. (A-1, X is I) Mp=125°-127° C. (dec). IR (mull) 3429, 3312, 3206, 2954, 2925, 2868, 2854, 1632, 1607, 1569, 1472, 1462, 1459, 1198, 984, 810, 675 cm-1 ; 1H NMR (CDCl3)δ6.48 (d, 2 H, J=2 Hz), 5.98 (t, 1 H, J=2 Hz), 3.78 (s, 4 H); 13C NMR (CDCl3) δ148.1, 114.6, 101.0, 94.9; Mass Spec (70eV, EI) m/z 234 (parent), 206, 117, 107 (base), 80, 66, 53, 42; Exact Mass calculated for C6H7IN2 : 233.9656. Found: 233.9652. Analysis Calculated for C6H7IN2 : C, 30.79; H, 3.02; N, 11.97; I, 54.22; Found: C, 30.93; H, 2.97; N, 11.71; I, 54.26.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[N:28][N:29]=1>>[S:26]1[CH:27]=[N:28][N:29]=[C:25]1[NH:24][C:1]([C:4]12[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]1)[CH2:6][CH2:5]2)=[O:3]
Reactant: Nc1nncs1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nncs3)(CC1)CC2
Yield: 33.3 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-1,3,4-thiadiazole (34.4 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.9 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]=[O:14]>O1CCOCC1>[CH2:15]([NH:12][C:13]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[N:2]([CH3:1])[C:3]1=[O:11])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN=C=O
Reactant: Cn1c(=O)[nH]c2ncccc21
Solvent: C1COCCO1
Product: CCCCCCNC(=O)n1c(=O)n(C)c2cccnc21

Procedure:
1-Methyl-1,3-dihydroimidazo[4,5-b]pyridin-2-one (75 mg, 0.5 mmol) and 1-isocyanatohexane (64 mg, 0.5 mmol) were stirred at 80° C. in 3.5 ml of dioxane for 4 h. The reaction mixture was concentrated and purified by means of preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 40 mg (29%), M+H+: 277.16.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[C:12]([CH2:14][C:15]([NH2:17])=[S:16])#[N:13]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:15]([CH2:14][C:12]#[N:13])[S:16][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: N#CCC(N)=S
Product: N#CCc1nc(-c2ccc(Cl)cc2)cs1
Yield: 75 %

Procedure:
This compound was synthesized from 2-bromo-1-(4-chlorophenyl)ethanone and 2-cyanothioacetamide as described in example 1 step 1 (1.51 g, yield 75%). 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 4.18 (s, 2H). MS (ESI) m/z: Calculated for C11H7ClN2S: 234.00. found: 235.0 (M+H)+.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1([NH:20][N:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC1C=CC(S([N-]Cl)(=O)=O)=CC=1.O.O.O.[Na+].CO>C(OCC)(=O)C>[C:14]1([N:20]2[CH:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:2]([C:1]([O:11][CH2:12][CH3:13])=[O:10])[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C(=NNc1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)C1C(c2ccccc2)=NN(c2ccccc2)C1c1ccccc1

Procedure:
A mixture of ethyl cinnamate (7, 2.55 g), benzaldehyde phenylhydrazone (2, 4.21 g), chloramine-T trihydrate (6.45 g), and methanol (45 mL) were heated under refluxing for 22 hours. The reaction mixture was diluted with 50% ethyl acetate in n-hexanes (400 mL), filtered, and evaporated. The residue was purified by column chromatography (silica gel 200 g, eluent: 0 to 10% ethyl acetate gradient in hexanes) and evaporated to give FN1-1 (8, 1.25 g) as colorless crystal. 1H NMR (CDCl3, 400 MHz) δ 7.66-7.64 (m, 1H), 7.46-7.22 (m, 13H), 6.88 (t, J=7.2 Hz, 1H), 4.81 (d, J=4.0 Hz, 1H), 4.70 (d, J=4.0 Hz, 1H), 4.07 (quartet, J=7.2 Hz, 2H), 0.97 (t, J=7.2 Hz, 3H). MS: 371.9 (M+H), 325.5, 297.5.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:8].[C:35]([NH2:38])(=[O:37])[CH3:36]>O>[C:35]([NH:38][C:10]([CH:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:18][CH:19]=1)[C:7]([O:6][CH3:5])=[O:8])=[O:12])(=[O:37])[CH3:36]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reactant: CC(N)=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)NC(C)=O
Temperature: 60 °C
Yield: 37.3 %

Procedure:
Thionyl chloride (1.0 ml) was added to 2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (2.63 g, 6.43 mmol) obtained in Example 1, and the mixture was stirred with heating at 60° C. for 1 hr. Excess thionyl chloride was evaporated under reduced pressure and acetamide (504 mg, 8.54 mmol) was added to the residue. The mixture was stirred with heating at 120° C. for 30 min. Tetrahydrofuran-ethyl acetate (1:1, 100 ml) and water (50 ml) were added to the reaction mixture for partition. The organic layer was washed with saturated brine (50 ml), dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (1.08 g, yield 34%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:6]([N+:10]([O-])=O)=[CH:7][C:8]=1[Br:9])[NH2:5].[H][H]>[Ni].C(O)C>[Br:1][C:2]1[C:8]([Br:9])=[CH:7][C:6]([NH2:10])=[C:4]([NH2:5])[CH:3]=1
Reactant: [H][H]
Reactant: Nc1cc(Br)c(Br)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(Br)c(Br)cc1N
Reaction time: 0.42 h

Procedure:
Five grams of 3,4-dibromo-6-nitroaniline were suspended in 200 ml. of anhydrous ethanol to which was added about 10 g. of Raney nickel. The hydrogenation mixture was placed in a low pressure hydrogenation apparatus at a hydrogen pressure of 55 psi. A rapid uptake of hydrogen occurred which ceased after about 25 minutes, at which time the deep yellow color originally present had been discharged indicating complete reduction of the nitro group to an amino group. The hydrogenation was continued for another half hour and the hydrogenation mixture was then worked up by filtering off the catalyst, washing the filtered catalyst, and stripping the volatile constituents from the filtrate. A yield of 4.1 g. of 4,5-dibromo-o-phenylenediamine was obtained.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].[CH2:13](Cl)Cl.CO.[Si](C=[N+]=[N-])(C)(C)C>C(O)(=O)C>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3]
Reactant: ClCCl
Reactant: C#CCC1CCC(C(=O)O)CC1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: C#CCC1CCC(C(=O)OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 88 (240 mg, 1.45 mmol) in 7:3 CH2Cl2:MeOH (10 mL) was added TMS Diazomethane (2.0 M in hexanes) (0.9 mL, 1.8 mmol) in 0.2 ml aliquots until the color remained yellow. The reaction was allowed to stir for an additional 0.25 hours at room temperature. After stirring, glacial acetic acid was added dropwise until the solution became colorless. The reaction was concentrated in vacuo to an oil which was purified by flash chromatography on silica gel using ether:petroleum ether (1:9) to yield 89 (210 mg, 80%) as a clear oil. 1H NMR (CDCl3) δ 3.60 (s, 3H), 2.25-2.13 (m, 1H), 2.08-1.94 (m, 3H), 1.95-1.90 (m, 2H), 1.49-1.31 (m, 3H), 1.10-0.93 (m, 2H); 13C NMR (CDCl3) δ 176.7, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3; APCI m/z (rel intensity) 181 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])([CH3:22])([CH3:21])[CH3:20]>CO.C(Cl)Cl>[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:26][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure B and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-leucine tert-butyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=128° C.). The reaction was monitored by tlc (Rf=0.85 in 5% MeOH/methylene chloride) and the product was purified by flash column chromatography using 5% MeOH/methylene chloride as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:26]
Reactant: O=C(Cl)c1ccco1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccco1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.35 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 13.05 g. of 2-furoyl chloride are reacted to produce the product as a dark brown gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38]1>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][C:25]([S:28][CH3:29])=[CH:26][CH:27]=4)[C@@H:19]([NH:21][S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1ccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NS(=O)(=O)C2CC2)cc1

Procedure:
(1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(methylthio)phenyl]propan-2-amine (29a, 100 mg, 0.24 mmol) was dissolved in MeCN (3 mL), triethylamine (0.104 mL, 0.75 mmol) was added followed by addition of cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol). The reaction was followed by LC/MS. After 1 hour approximately 50% conversion was detected, more reagents cyclopropane sulfonylchloride (0.025 mL, 0.25 mmol) and triethylamine (0.07 mL, 0.50 mmol) were added in an attempt to increase conversion without any success. The reaction was quenched by addition of saturated NH4Cl (aq) and concentrated. The residual material was purified by HPLC, collected fractions was freeze dried to give the title compound as a colourless solid. Chiral HPLC was made using an Chiralpak IB™, 150×0.46 mm column, 15% EtOH in iso-Hexane, 0.5 mL/min, UV=254 nm, one major peak at 32.39 min (99.7%) and one minor peak at 30.69 min (0.3%).
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].N[CH2:7][C@@H:8]1CC[CH2:10][N:9]1CC>>[CH3:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:7][CH2:8][NH:9][CH3:10]
Reactant: CNC(C)C
Reactant: CCN1CCC[C@H]1CN
Product: CNCCN(C)C(C)C

Procedure:
By using N-isopropylmethylamine (844.7 mg) as a starting material, the title compound (58 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.S1C(C(O)=O)=CC2C=CC=CC1=2.C(Cl)(=O)C(Cl)=O.[NH2:31][CH:32]([P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.N1C=CC=CC=1>[S:1]1[C:5]([C:6]([NH:31][CH:32]([P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(NC(=O)c1cc2ccccc2s1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-benzo[b]thiophenecarbonyl chloride prepared from 2-benzo[b]thiophenecarboxylic acid (356 mg) and oxalyl chloride (0.35 ml) in methylene chloride (2 ml) was added dropwise a mixture of tetraethyl (aminomethylene)bis(phosphonate) (606 mg), pyridine (316 mg) and trace amounts of 4-(dimethylamino)pyridine in methylene chloride (8 ml) at 5° C. The mixture was stirred for 2 hours at ambient temperature followed by the addition of ethyl acetate. The mixture was washed with water, 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was treated with diisopropyl ether to give tetraethyl [(2-benzo[b]thiophenecarboxamido)methylene]bis(phosphonate) (790 mg) as a white powder which was recrystallized from a mixture of ethyl acetate and n-hexane.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Cl:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([S:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: Cc1cc(OCCCCSc2ccc(Cl)c(Cl)c2)cc2c1NC(=O)OC2(C)C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichlorothiophenol.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][S:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])[CH:16]=1)(=[O:13])=[O:12]>C(OCC)C.[OH-].[Na+]>[CH3:10][S:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:17]([C:22]([CH3:26])([CH3:25])[CH2:23][O:24][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=1)(=[O:13])=[O:12]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(COC(=O)c1ccccc1)c1cc(OS(C)(=O)=O)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl chloride (5.6g) in diethyl ether (50 ml) was added dropwise with vigorous stirring to a solution of 3-(2-hydroxy-1,1-dimethylethyl)-4-hydroxyphenyl methanesulphonate in aqueous sodium hydroxide solution (1.6g in 100 ml water). The mixture was stirred for three hours at room temperature, then separated, and the ether solution washed with dilute sodium hydroxide solution followed by water. Drying over magnesium sulphate and running down gave 4.5g of an oil. Crystallization from ethanol gave 0.7g of 3-(2-benzoyloxy-1,1-dimethyl-ethyl)-4-benzoyloxyphenyl methanesulphonate, m.p. 100°-101° C. Removal of the solvent from the mother liquors gave 2.5g of 3-(2-benzoyloxy-1,1-dimethyl-ethyl)-4-hydroxyphenyl methanesulphonate as a viscous oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCN1
Product: CC(=O)N1CCCC1=O
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 112 g of 2-pyrrolidinone (9) and 249 mL of acetic anhydride was heated at reflux for 2 hours. The resultant mixture was allowed to cool to room temperature, was concentrated in vacuo, and was distilled (0.8 mm Hg, 68° C.) to provide 160 g of N-acetyl-2-pyrrolidinone (4) in 96% yield.
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([NH2:11])=[O:10])[C:5]=1[N+:12]([O-])=O)([CH3:3])[CH3:2].CO>[Ni].O>[NH2:12][C:5]1[C:6]([C:9]([NH2:11])=[O:10])=[N:7][NH:8][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)c1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(C)c1[nH]nc(C(N)=O)c1N
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of 5-isopropyl-4-nitropyrazol-3-carboxamide (2.57 g; 12.97 mmol), methanol (20 mL) and water (5 mL) was added 0.7 g Raney Ni (W5). The mixture was stirred under hydrogen atmosphere (760 torr) for four hours. The reaction mixture was filtered, the filtrate was concentrated to dryness in vacuo and the residue was recrystallized from ethyl acetate to yield 1.94 g (89%) of the product. The product was purified by chromatography on silica gel, the mixture of chloroform/methanol (97/3) was used as mobile phase. Yield 95%; mp=178-179° C.; MS (ES+): 169.1 (100%, M+H+). 1H NMR (CD3OD; 400 MHz): 1.31 d (6H; J=7.5 Hz), 3.06 sept (1H; J=7.5 Hz), 4.83 s (2H).
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C1C=CC=CC=1.[H][H].C(Cl)Cl.CO>C(O)C.CO.Cl.[Pd]>[Si:23]([O:22][CH2:21][C@@H:10]([O:11][CH2:12][P:13](=[O:20])([O:14][CH2:15][CH3:16])[O:17][CH2:18][CH3:19])[CH2:9][OH:8])([C:36]([CH3:38])([CH3:39])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOP(=O)(CO[C@@H](COCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOP(=O)(CO[C@@H](CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OCC
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of diethyl (S)-[2-benzyloxy-1-(t-butyldiphenylsilyloxymethyl)ethoxy]methylphosphonate (1.90 g, 3.3 mmol) in ethanol (20 ml) containing a trace of methanol/HCl (10 drops), was added 10%Pd-C (1.2 g). The mixture was shaken under an atmosphere of hydrogen at ambient temperature and atmospheric pressure until hydrogen uptake was complete and t.l.c. (SiO2, CH2Cl2 -MeOH, 95:5) indicated no starting material remained. The reaction mixture was filtered, the filtrate evaporated and the residue obtained chromatographed on silica gel (dichloromethanemethanol, 95:5 as eluant) to give the title compound as a colourless oil (1.35 g, 84%).