Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[C:17]([O:21][C:22](=[O:32])[NH:23][CH:24]1[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22](=[O:32])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH:30]([OH:31])[C:10]2[S:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)[CH2:28][CH2:29]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Reactant: COc1cccc2scnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2sc(C(O)[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc12

Procedure:
To a solution of 4-methoxy-benzothiazole (1.65 g, 10 mmol) in THF (50 ml) was added dropwise n-BuLi (2.5M in hexanes, 4 ml) so that the temperature did not exceed −70° C. The brown solution was stirred at this temperature for 15 min before dropwise addition of a solution of (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.14 g, 5 mmol) in THF (10 ml). The temperature was kept below −70° C. The brown solution was then gradually allowed to reach RT (over 3 h). The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 and concentrated under reduced pressure. The product was crystallised from ether to give 1.04 g (53%) of a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[Br:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=3[O:12][CH3:13])[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccc(OC)c2c(Cl)c(C#N)cnc12
Reactant: Nc1cccc(Br)c1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(OC)c2c(Nc3cccc(Br)c3)c(C#N)cnc12
Yield: 93.1 %

Procedure:
A mixture of 0.148 g of 4-chloro-5,8-dimethoxy-3-quinolinecarbonitrile, 0.12 g of m-bromoaniline, and 5 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 50 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, dried, and washed with 10 ml of hexanes-ethyl acetate (4:1) to give 0.213 g of 4-(3-bromo-phenylamino)-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 72-74° C.; mass spectrum (EI, m/e): M 383.0265.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[F:17])[C:5]([C:18]#[N:19])=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>O1CCCC1.C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([F:17])=[C:8]([C:6]2[C:5]([C:18]#[N:19])=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[CH:13]=1
Reactant: N#Cc1ccc(F)cc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(F)cc1-c1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5,2′-Difluoro-5′-nitrobiphenyl-2-carbonitrile (3.25 g, 12.5 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was treated with tin(II) chloride dihydrate (9.86 g, 43.8 mmol) and the mixture left to stir at ambient temperature for 18 h. The solvent was evaporated and the residue stirred with 2 N sodium hydroxide solution (40 ml) for 2 h. The resulting suspension was diluted with water (100 ml) and extracted with dichloromethane (3×200 ml). The combined organics were washed with water (200 ml), brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound as a brown solid: 1H NMR (360 MHz, CDCl3) δ 3.68 (2H, s), 6.67-6.76 (2H, m), 7.02 (1H, dd, J 9, 9 Hz), 7.12-7.27 (2H, m), 7.78 (1H, dd, J 9, 6 Hz).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[C:21]([C:23](=[O:30])[NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH:20]=[C:19]([O:31][CH:32]([CH3:34])[CH3:33])[CH:18]=2)=[N:12][CH:11]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[C:21]([CH:20]=[C:19]([O:31][CH:32]([CH3:34])[CH3:33])[CH:18]=2)[C:23]([NH:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)=[O:30])=[N:12][CH:11]=1
Reactant: COC(=O)c1ccc(Oc2cc(OC(C)C)cc(C(=O)Nc3nccs3)c2)nc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(Oc2ccc(CO)cn2)cc(C(=O)Nc2nccs2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
After adding 6.0 mg (0.16 mmol) of lithium aluminum hydride to a solution of 60.0 mg (0.15 mmol) of the 6-[3-isopropoxy-5-(thiazol-2-ylcarbamoyl)-phenoxy]-nicotinic acid methyl ester obtained in Production Example 65 in tetrahydrofuran (5.0 ml) while cooling on ice, the mixture was stirred at 0° C. for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=30:1) to obtain the title compound as a white solid. The analysis data for the compound obtained in Production Example 66 are shown below.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:31])[CH:19]=1)[C:12](OCC)=O)=[O:10].C(O)(C)C>CO.O>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:20](=[O:31])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)C(C=O)Cc1ccn(Cc2ccccc2)c(=O)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Yield: 36.8 %

Procedure:
To a stirred solution of sodium (2.76 g) in methanol (50 ml) was added nitroguanidine (11.10 g. containing 25% water) and methanol (10 ml). The mixture was refluxed for 45 minutes and then ethyl α-formyl-β-(N-benzyl-2-oxo-4-pyridyl)propionate (25.07 g) in methanol (90 ml) was added over one hour. The reaction mixture was refluxed for 24 hours, cooled and evaporated under reduced pressure to afford an oily residue which was dissolved in water (100 ml). The solution was extracted with chloroform (3×50 ml) and the combined chloroform extracts were washed with water (3×25 ml). The combined aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid to give an oily solid. Isopropanol (35 ml) was added with warming to cause dissolution, on cooling a solid formed which was collected by filtration, washed with water, washed with isopropanol and recrystallised from water-acetic acid to give white crystals of 2-nitroamino-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (10.40 g), m.p. 200°-201° C.
Reaction SMILES: [OH-:1].[K+].[NH2:3][CH2:4][C:5]1[C:10]2[N:11]([CH3:14])[CH:12]=[N:13][C:9]=2[CH:8]=[C:7]([C:15]#[N:16])[C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].Cl>OO.CO>[NH2:3][CH2:4][C:5]1[C:10]2[N:11]([CH3:14])[CH:12]=[N:13][C:9]=2[CH:8]=[C:7]([C:15]([NH2:16])=[O:1])[C:6]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23]
Reactant: [OH-]
Reactant: Cn1cnc2cc(C#N)c(-c3ccccc3Cl)c(CN)c21
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CO
Product: Cn1cnc2cc(C(N)=O)c(-c3ccccc3Cl)c(CN)c21
Reaction time: 16 h
Yield: 68.2 %

Procedure:
A solution of KOH (30 mg, 0.54 mmol) in 30% H2O2 (2 mL) was added to a solution of Example 23 (80 mg, 0.27 mmol) in methanol (6 mL) at r.t. After stirring for 16 h, the solution was neutralized with 1N HCl and concentrated in vacuo. Purification by Prep-HPLC yielded 58 mg (50%) of the title compound as a white solid. 1H NMR (400 MHz, MeOD-d4): δ 9.19 (s, 1H), 8.10 (s, 1H), 7.43-7.60 (m, 4H), 4.41 (qAB, 2H, J=158.8, 14.8 Hz), 4.32 (s, 3H). MS (ES) [m+H] calc'd for C16H15N4OCl, 315, 317; found 315, 317.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[CH:9]([OH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].O>CC(C)=O>[C:1]([CH2:3][CH:4]([OH:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16])#[N:2]
Reactant: N#CCC(O)Cc1cccc(C(O)c2ccccc2)c1
Solvent: O
Solvent: CC(C)=O
Product: N#CCC(O)Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.08 h

Procedure:
7.35 ml of a sulfochromic mixture titrating 26.5 g of chromic anhydride per 100 ml was added with stirring at 0°C to 7.8 g of 3-(3'-cyano-2'-hydroxypropyl)-benzhydrol in 78 ml of acetone and the mixture was allowed to stand at 0°C for 5 minutes and was then poured into water with stirring. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried over sodium sulfate, treated with activated carbon, filtered and evaporated to dryness to obtain 7.4 g of 3-(3'-cyano-2'-hydroxypropyl)-benzophenone which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14](I)([CH3:16])[CH3:15].O.[OH-].[Na+]>C(O)C>[F:1][C:2]1[C:10]([O:11][CH:14]([CH3:16])[CH3:15])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(F)c(O)c1F
Reactant: CC(C)I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Oc1c(F)c(F)cc(C(=O)O)c1F

Procedure:
2,4,5-Trifluoro-3-hydroxybenzoic acid (4.0 g) was added together with isopropyl iodide (4.7 g) to a mixed liquid of distilled water (10 ml) and ethanol (20 ml), in which sodium hydroxide (1.83 g) had been dissolved. The mixture was stirred and heated under reflux for 23 hours. The reaction mixture was concentrated under reduced pressure. The resultant residue was acidified with concentrated hydrochloric acid, and water (25 ml) was added to conduct extraction twice with chloroform (25 ml). A collected chloroform layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to column chromatography (silica gel: 75 g, eluent; chloroform: methanol:acetic acid=500:20:1) to obtain 2,4,5-trifluoro-3-isopropyloxybenzoic acid as a solid residue.
Reaction SMILES: [C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[C:1]1([CH:7]([NH:9][CH2:10][CH:12]([OH:14])[CH2:13][NH:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCC1CO1
Reactant: CC(N)c1ccccc1
Product: CC(NCC(O)CNC(C)c1ccccc1)c1ccccc1

Procedure:
The racemate of α-phenylethylamine (1) was used as starting material and condensed with epichlorohydrin in the absence or presence of a solvent to obtain the racemate of 1,3-bis-[(1-phenylethyl)amino]-2-propanol (2) which was then cyclized with cyclizing reagents to give racemic 1,3-oxazolidin-2-one (I). Further reaction with an appropriate acid would give a salt of 1,3-oxazolidin-2-one (I).
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20](C)(C)[C:21](OCC)=[O:22])=O)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]2[CH2:20][C:21](=[O:22])[N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]=2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)N1N=C(c2ccc(Cl)cc2)CC1=O
Yield: 70.7 %

Procedure:
After 1.5 g (12 mmol) of t-butylhydrazine hydrochloride was stirred in 30 ml of acetic acid which contains 0.97 g (12 mmol) of sodium acetate for 30 minutes, 2.0 g (7.9 mmol) of ethyl α-(4-chloro-benzoyl)isobutyrate was added thereto, and the mixture was heated under reflux for 20 hours. Acetic acid was evaporated under reduced pressure, and to the obtained residue was added 50 ml of diethyl ether and 50 ml of water, and then vigorously agitated. The resulting solution was separated, and the aqueous layer was extracted twice with 50 ml of diethyl ether. The organic layer was combined and washed successively with water, 1N hydrochloric acid and saturated brine solution, and dried over anhydrous sodium sulfate. Then the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1 (v/v)) to give 1.4 g of the object compound as white crystals (yield 68%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])(=O)[CH3:2].Cl.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:23]=[C:24]([O:28][NH2:29])[CH:25]=[CH:26][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([NH:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:4]([C:1](=[N:29][O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:30])[CH:23]=2)[CH3:2])[CH:9]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1cccc(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NOc1cccc(C(F)(F)F)c1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 90.6 %

Procedure:
A solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (310 mg, 1.03 mmol), O-(3-trifluoromethylphenyl)hydroxylamine hydrochloride (220 mg, 1.03 mmol) and anhydrous NaOAc (93 mg, 1.13 mmol) in EtOH (18 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:5) afforded N-{4-chloro-2-[1-(3-trifluoromethylphenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 134 (430 mg, 91%), as a pale yellow solid. M.p. 63-64° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.00, br s, 1H; 7.71, d, J=9.0 Hz, 1H; 7.60, d, J=2.2 Hz, 1H; 7.56-7.35, m, 5H; 2.58, s, 3H. O-(3-Trifluoromethylphenyl)hydroxylamine hydrochloride was prepared in two steps by the procedure of Petrassi, M. H.; Sharpless, K. B.; Kelly, J. W. Org. Lett., 2001, 3, 139-142.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[N:23]1>>[N:22]1([C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:1]3[CH2:2][CH2:3][C:4]4([O:11][C:10]5[C:12]6[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=5[S:8][CH2:7]4)=[CH:16][CH:15]=[CH:14][CH:13]=6)[CH2:5][CH2:6]3)=[O:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccc(-n2cccn2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccc(-n4cccn4)cc3)CC1)O2

Procedure:
Compound 44 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(1H-pyrazol-1-yl)benzoyl chloride and conditions outlined in procedure N. M.p.=299-300° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.06 (d, 1H), 8.0 (s, 1H), 7.64 (m, 4H), 7.65 (t, 1H), 7.50 (m, 3H), 6.52 (s, 1H), 3.42 (m, 2H), 2.96 (s, 2H), 2.22 (m, 2H), 1.92 (m 2H), 1.58 (s, 2H); LCMS: 472 [M+H].
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:33][CH2:32]1.[NH2:43][C:44]1[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][C:47]([CH2:54][C@@H:55]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:56](O)=[O:57])=[CH:46][C:45]=1[Cl:67]>C1COCC1>[NH2:43][C:44]1[C:49]([C:50]([F:51])([F:52])[F:53])=[CH:48][C:47]([CH2:54][C@@H:55]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:56]([N:40]2[CH2:41][CH2:42][CH:37]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)[CH2:38][CH2:39]2)=[O:57])=[CH:46][C:45]=1[Cl:67]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OCc2ccccc2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.35 g (4.20 mmol) TBTU, 0.70 mL (5.0 mmol) triethylamine and 0.75 g (4.01 mmol) 1-methyl-4-piperidin-4-yl-piperazine were added to a solution of 1.5 g (4.01 mmol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-benzyloxy-propionic acid in 50 mL THF and the reaction mixture was stirred overnight at RT. The reaction solution was evaporated down i.vac., the residue was combined with 200 mL EtOAc and 200 mL saturated NaHCO3 solution, the organic phase was separated off and extracted with 100 mL of 5% citric acid solution. The citric acid extract was made alkaline with K2CO3 and extracted twice with 100 mL EtOAc in each case. The combined organic phases were evaporated down i.vac. and the residue further reacted without purification.
Reaction SMILES: [CH2:1]1[O:43][C:42]2[CH:41]=[CH:40][C:5]([CH2:6][N:7]([S:27]([C:30]3[C:35]([CH3:36])=[CH:34][C:33]([O:37][CH3:38])=[CH:32][C:31]=3[CH3:39])(=[O:29])=[O:28])[C@H:8]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])[C:9](O)=[O:10])=[CH:4][C:3]=2[O:2]1.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:44]([O:51][NH:52][C:9](=[O:10])[C@H:8]([N:7]([CH2:6][C:5]1[CH:40]=[CH:41][C:42]2[O:43][CH2:1][O:2][C:3]=2[CH:4]=1)[S:27]([C:30]1[C:31]([CH3:39])=[CH:32][C:33]([O:37][CH3:38])=[CH:34][C:35]=1[CH3:36])(=[O:28])=[O:29])[CH2:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26]1)=[O:15])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)O)c(C)c1
Reactant: NOCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)NOCc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 53 %

Procedure:
To a mixture of 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionic acid (approximately 1.3 mmol), O-benzylhydroxylamine (0.6 ml, 3.9 mmol) and 1-hydroxybenzotriazole hydrate (199 mg, 1.3 mmol), and N-methylmorpholine (0.44 ml, 3.9 mmol) in anhydrous dimethylformamide (20 ml) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimide hydrochloride salt (375 mg, 1.95 mmol). The mixture was stirred overnight and then condensed on the roto-evaporator. The remainder was taken up in ethyl acetate (60 ml) and partitioned with an equal volume of 1.5% aqueous hydrochloric acid. The ethyl acetate phase was collected and washed consecutively with equal volumes of 5% sodium bicarbonate and then brine. The aqueous phases were back extracted with ethyl acetate (2×60 ml) and the organic layers combined, dried with magnesium sulfate, filtered and condensed. The residue was purified by preparative TLC (2% methanol-methylene chloride) providing N-benzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionamide as a light yellow foamy solid (490 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](O)[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O.CN(C)C1C=CC=CC=1>>[Cl:20][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Clc1ccc(-c2cc(Cl)n3nccc3n2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
A mixture of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-ol (4.8 g, 19.5 mmol), phosphorous oxychloride (7.2 mL, 78 mmol), and N,N-dimethylaniline (0.87 mL, 7.0 mmol) was stirred at 100° C. for 2 h. The mixture was evaporated in vacuo and the residue was partitioned between water and dichloromethane. The organic phase was washed with water, dried (Na2SO4), and evaporated in vacuo. The remaining solid was crystallized from EtOAc to give 7-chloro-5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine (3.50 g, 66%) as a yellow solid; mp 151-153° C.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.C(N(CC)CC)C.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([NH:1][C:2]1[S:3][C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[C:5]([C:7]([F:10])([F:9])[F:8])([C:11]([F:12])([F:13])[F:14])[N:6]=1)=[O:34]
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1)c1cccc(C(F)(F)F)c1
Temperature: 103 °C
Reaction time: 3 h

Procedure:
In toluene (40 ml) were dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (2.0 g) and triethylamine (1.0 ml), and a solution of 3-trifluoromethylbenzoyl chloride (1.5 g) dissolved in toluene (10 ml) was gradually added thereto under cooling and the mixture was stirred at 103° C. for 3 hours.
Reaction SMILES: Cl.[NH2:2][C:3]([C:6]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]([OH:24])[N:7]=1)([CH3:5])[CH3:4].CCN(CC)CC.[Cl:32][CH2:33][CH:34]=O.CC(O)=O.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O>[Cl:32][CH2:33][CH2:34][NH:2][C:3]([C:6]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]([OH:24])[N:7]=1)([CH3:4])[CH3:5]
Reactant: CC(C)(N)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Reactant: O=CCCl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(NCCCl)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a methanolic solution of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide hydrochloride (prepared as described in WO2003035076 A1) Et3N (1 eq.), chloroacetaldehyde (2 eq.), AcOH (ca. 1.5 eq.) were added and subsequently NaBH3CN (1.5 eq.). The reaction mixture was stirred at room temperature overnight. To drive the reaction to completion a few drops of TFA were added and stirring was prolonged for a further 1.5 hours. MeOH was removed under reduced pressure to yield the title amine as crude. MS (ES) C17H20ClFN4O3 requires 383. Found: 384 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[NH:7])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18]N)=O)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[N:8]=[C:16]([C:15]3[CH:20]=[CH:21][C:12]([F:11])=[CH:13][CH:14]=3)[NH:18][N:7]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(F)cc1
Reactant: N=C(N)c1ccc(F)cc1
Product: Fc1ccc(-c2n[nH]c(-c3ccc(F)cc3)n2)cc1
Yield: 71.2 %

Procedure:
4 g 4-fluoro-benzamidine was mixed with 4.5 g 4-fluoro-benzoic acid hydrazide and the mixture was melted. Then the mixture was crystallized from ethyl acetate to yield 5.3 g of the desired compound. Rt: 1.55 min (method A), (M+H)+: 258
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][N:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:10]([CH3:13])[CH:11]=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28](=[O:41])[C@@H:29]([NH2:40])[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:26][O:27][C:28](=[O:41])[C@@H:29]([NH:40][CH2:11][C@H:10]([N:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[CH3:13])[CH2:30][CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)[C@@H](N)CCOCc1ccccc1
Reactant: C[C@H](C=O)N(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](CCOCc1ccccc1)NC[C@@H](C)N(CCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
In analogy to the procedure described in example 58D, 3-[benzyloxycarbonyl-((R)-1-methyl-2-oxo-ethyl)-amino]-propionic acid tert-butyl ester and (S)-2-amino-4-benzyloxy-butyric acid methyl ester hydrochloride (intermediate 7) gave the title compound in quantitative yield as yellow oil. MS: 543.5 (MH+).