Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.S(OC)(O[CH3:14])(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:14])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COS(=O)(=O)OC
Product: COc1ccc(Cl)c(C)c1

Procedure:
4-Chloro-m-cresol was methylated with dimethyl sulfate to give 1-chloro-4-methoxy-2-methylbenzene. This was converted with N -bromosuccinimide into 2-bromomethyl- 1-chloro-4-methoxybenzene. Subsequent alkylation with diethyl malonate yielded diethyl (2-chloro -5-methoxy-benzyl)-malonate. This was condensed with morpholine -formamidine in analogy to Example 1, part d), to give 5-(2-chloro-5-methoxy-benzyl)-2-(morpholin-4-yl)-4,6(1H,5H)-pyrimidinedione. Subsequent chlorination with POCl3 analogously to Example 1e) gave 4,6-dichloro-5-(2-chloro-5-methoxy-benzyl)-2-(morpholin-4-yl)-pyrimidine which was reacted further with (4-tert.butylbenzenesulfonamide) K analogously to Example 1 g) to give 4-tert-butyl-N-[6-chloro-5-(2-chloro -5 -methoxy-benzyl)-2-(morpholin-4-yl)-pyrimidin-4-yl]benzenesulfonamide. Subsequent reaction with sodium ethylene glycolate analogously to Example 1h) finally gave 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-chloro-5-methoxybenzyl)-2-(morpholine-4-yl)pyrimidin-4-yl]-benzenesulfonamide. M.p. 159°-162° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:33]=1)[C:28](O)=[O:29])#[N:24]>>[C:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:34][C:35]([F:36])([F:38])[F:37])[CH:33]=1)[C:28]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:29])#[N:24]
Reactant: N#Cc1cc(OC(F)(F)F)cc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Product: Cc1ccc(NC(=O)c2cc(C#N)cc(OC(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
Analogously to the procedure for Example 33, 50 mg (0.17 mmol) of the compound of Example 6A and 40 mg (0.18 mmol) of the compound of Example 41A were reacted with one another. After purification of the crude product by preparative HPLC, the product-containing fractions were concentrated to a small residual volume and made alkaline with a little saturated aqueous sodium bicarbonate solution. The precipitate formed was filtered off, washed with water and dried. This gave 56 mg (65% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][P:27]([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[C:33]([O:38][CH3:39])[CH:32]=2)(=[O:30])[CH2:26][CH2:25]1)[CH3:23].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([P:27]3(=[O:30])[CH2:28][CH2:29][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26]3)=[CH:32][C:33]=2[O:38][CH3:39])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: CCN1CCP(=O)(c2ccc(N)c(OC)c2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: CCN1CCP(=O)(c2ccc(Nc3nnc(Cl)c(Nc4ccccc4S(=O)(=O)C(C)C)n3)c(OC)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:10]2)=[CH:5][C:4]([C:23]([OH:25])=O)=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C([O:55][C:56](=[O:70])[C@@H:57]([NH:60][S:61]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=[O:63])=[O:62])[CH2:58][NH2:59])(C)(C)C.N1C(C)=CC(C)=CC=1C>>[C:64]1([S:61]([NH:60][C@@H:57]([CH2:58][NH:59][C:23]([C:4]2[CH:5]=[C:6]3[N:11]([C:2](=[O:1])[CH:3]=2)[CH:10]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH:8]=[CH:7]3)=[O:25])[C:56]([OH:70])=[O:55])(=[O:62])=[O:63])[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: O=C(O)c1cc(=O)n2cc(OCCCNc3ncccn3)ccc2c1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1cc(=O)n2cc(OCCCNc3ncccn3)ccc2c1
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
To a mixture of 4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carboxylic acid (6.9 mg, 0.020 mmol), was added HATU (9.9 mg, 0.026 mmol), (S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl ester hydrochloride (8.1 mg, 0.024 mmol) and collidine (19 μl, 0.140 mmol). The mixture was stirred for 45 minutes, concentrated and flash chromatographed (0-5% methanol in dichiloromethane) to give 10.3 mg (82% yield) of desired product.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=O)[O:5]C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[C@H:24]([CH3:25])[O:23]3)=[N:16]2)=[CH:11][CH:10]=1.O>CS(C)=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]3[O:23][C:4](=[O:5])[N:3]([O:2][CH3:1])[CH:24]3[CH3:25])=[N:16]2)=[CH:13][CH:14]=1
Reactant: C[C@@H]1O[C@@H]1COc1ccn(-c2ccc(Cl)cc2)n1
Reactant: CONC(=O)OC
Solvent: CS(C)=O
Solvent: O
Product: CON1C(=O)OC(COc2ccn(-c3ccc(Cl)cc3)n2)C1C
Temperature: 25 °C

Procedure:
To 1.08 g (10.0 mmol) methyl N-methoxycarbamate in 17 ml DMSO have been added with stirring at ambient temperature 1.00 g (8.9 mmol) potassium tert.-butylate. Stirring has been continued for 5 min before 2.00 g (7.56 mmol) 1-(4-chloro-phenyl)-3-[[(2R,3S)-3-methyloxiran-2-yl]methoxy]pyrazole have been added. The mixture was stirred at 90° C. for 20 h. After cooling to ambient temperature the reaction mixture was poured into 150 ml of water, extracted thrice with 30 ml ethyl acetate each, the combined extracts have been dried with sodium sulfate and the solvent removed in vacuo. The crude product (2.5 g) was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)([OH:39])[CH2:35][CH2:34]1.O>CN(C=O)C.C(Cl)Cl>[OH:39][C:36]1([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:14][C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH2:34][CH2:35]1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(CC2(O)CCN(CCO)CC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CC2(O)CCN(CCOC(=O)c3ccc(OCc4ccccc4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.1 %

Procedure:
4-Benzyloxybenzoic acid (0.685 g, 3 mmol) was dissolved in DMF (6 ml), and 1,1,-carbonyldiimidazole (0.58 g, 3.6 mmol) was added portionwise. The reaction mixture was heated to 55°-60° C. for 20 min. and then cooled to room temperature. A solution of 1-(2-hydroxy-ethyl)-4-(4-methyl-benzyl)-piperidin-4-ol (0.78 g, 3.3 mmol) in DMF (2 ml) was added. The reaction mixture was stirred 23 hours at room temperature and 4 hours at 60° C. H2O (50 ml) was added followed by CH2Cl2. Organic phase was washed with sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (CH2Cl2 --MeOH, 19:1) to provide 4-benzyloxy-benzoic acid 2-[4-hydroxy-4-(4-methyl-benzyl)-piperidin-1-yl]-ethyl ester (0.65 g, 47%) as a colorless solid, m.p. 102° C. and MS: m/e=460.3 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[O:7][C:6]2[C:14](F)=[C:15]([F:18])[CH:16]=[CH:17][C:5]=2[NH:4][C:3]1=[O:20].[NH4+].[Cl-].FC1C=C(F)C=CC=1[N+]([O-])=O>[Zn]>[NH2:1][CH:2]1[C:8]2([CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[O:7][C:6]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:5]=2[NH:4][C:3]1=[O:20]
Reactant: NC1C(=O)Nc2ccc(F)c(F)c2OC12CCOCC2
Agent: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Cl-]
Agent: [NH4+]
Product: NC1C(=O)Nc2ccc(F)cc2OC12CCOCC2
Reaction time: 6 h

Procedure:
In a similar manner to that described for the preparation of 3-amino-8,9-difluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one except in step 2 2.5 eq. of NH4Cl and 12 eq. of Zn were used, in step 3 the mixture was stirred for 6 h and in step 4 the mixture was hydrogenated overnight, 2,4-difluoronitrobenzene (2.69 g, 1.79 mL, 16.9 mmol) was converted to the title compound as a beige solid (110 mg) which was used without purification.
Reaction SMILES: [CH2:1]1[C:10]2=[CH:11][CH:12]=[CH:13][C:8]3=[C:9]2[N:4]([C:5](=[O:14])[CH2:6][CH2:7]3)[C:3](=[O:15])[CH2:2]1.Cl.[C:17]1([CH2:23][OH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][O:24][C:3](=[O:15])[CH2:2][CH2:1][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[NH:4][C:5](=[O:14])[CH2:6][CH2:7]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCc2cccc3c2N1C(=O)CC3
Reactant: OCc1ccccc1
Agent: Cl
Product: O=C1CCc2cccc(CCC(=O)OCc3ccccc3)c2N1

Procedure:
A solution of 1,2,6,7-tetrahydro-3H,5H-benzo-[ij]-quinolizine-3,5-dione (20.1 g, 0.1 mole) in phenylmethanol (200 ml) is treated with a drop of concentrated hydrochloric acid. The mixture is refluxed 24 hours (or until the starting dione can no longer be detected by thin layer chromatography). The solution is cooled and concentrated at reduced pressure. The product is purified by flash chromatography to yield 1,2,3,4-tetrahydro-2-oxo-8-quinoline propanoic acid phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C1(C)C=CC=CC=1.O>CCOC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]
Reactant: CCOP(=O)(CN)OCC
Reactant: O=Cc1ccccc1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(CN=Cc1ccccc1Cl)OCC
Reaction time: 0.5 h
Yield: 100 %

Procedure:
14 g. (0.1 mol) 2-Chlorobenzaldehyde are added dropwise at ambient temperature to a solution of 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. toluene. When the addition has ended, stirring is continued for 30 minutes. The water formed during the reaction is removed by decantation. The toluene phase is washed with 50 ml. of a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and then evaporated to give 29 g. (yield: 100%) diethyl N-(o-chlorobenzylidene)-aminomethylphosphonate in the form of a yellow oil giving a single spot in TLC (silica plate, eluant: AcOEt, rf=0.45).
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:3].[C:13](ON1C(=O)CCC1=O)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1COCC1>[CH3:3][C:2]([NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:1]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(N)CCN1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(CCN1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49.6 %

Procedure:
To a solution of crude 2-methyl-4-(piperidin-1-yl)butan-2-amine in THF (100 mL) was added CbzOSu (8.10 g, 1.2 equiv, 33.2 mmol) in one portion. The reaction mixture was left to stir at room temperature for 17 h. The solvent was removed under reduced pressure and the residue was taken up in a mixture of ethyl acetate (300 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 5% ethyl acetate in hexanes to 100% ethyl acetate. The desired fractions were collected and concentrated to give a pale yellow oil (4.91 g, 49.6%). 1H NMR (CDCl3, 400 MHz): δ 1.36 (s, 6H), 1.37-1.45 (m, 2H), 1.51-1.53 (m, 6H), 2.30-2.45 (m, 6H), 2.38 (s, 2H), 5.05 (s, 2H), 7.27-7.36 (m, 5H). LRMS (ESI+) for C18H28N2O2 (304.2); Found: 305 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:14])[CH2:10][S:11]([CH3:13])=[O:12].[N:15]([O-])=O.[Na+].ClC1C=C2C(=CC=1)NN=C(S(C)=O)C2=O>Cl>[CH3:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][N:15]=[C:10]([S:11]([CH3:13])=[O:12])[C:9]2=[O:14]
Reactant: O=N[O-]
Reactant: Cc1ccc(N)c(C(=O)CS(C)=O)c1
Agent: CS(=O)c1n[nH]c2ccc(Cl)cc2c1=O
Agent: Cl
Agent: [Na+]
Product: Cc1ccc2[nH]nc(S(C)=O)c(=O)c2c1

Procedure:
This compound was prepared by diazotizing a solution of 18.5 g of 2'-amino-5'-methyl-2-(methylsulfinyl)acetophenone in 500 ml of 1N HCl with 6.3 g of NaNO2 in analogous fashion to 6-chloro-3-(methylsulfinyl)-4(1H)-cinnolinone. The material was recrystallized from DMF, m.p. 265°-67°; yield 15 g (77%).
Reaction SMILES: [H-].[Na+].[F:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:18][CH:19]([N:21]1[C:30]2[C:25](=[CH:26][C:27]([C:31](=O)[CH3:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)[CH3:20].[Cl-].[NH4+]>CN(C)C=O>[CH3:20][CH:19]([N:21]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:32])=[C:4](/[F:3])\[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1)[CH3:18]
Reactant: CC(=O)c1ccc2c(c1)CCCN2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(F)=C(/C)c1ccc2c(c1)CCCN2C(C)C
Yield: 81.9 %

Procedure:
450 mg (60%, 12 mmol) of sodium hydride was suspended in 10 ml of N,N-dimethylformamide. 3.3. g (14 mmol) of ethyl 2-fluoro-diethylphosphonoacetate was dropped into the suspension under cooling with ice. The obtained mixture was stirred under cooling with ice for 30 minutes, followed by the addition of 2.0 g (9.2 mmol) of 1-[1-(1-methylethyl)-1,2,3,4-tetrahydroquinolin-6-yl)ethanone. The obtained mixture was stirred under cooling with ice for onie hour, followed by the addition of an aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography to give 2.3 g of the title compound as a colorless oil.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C@@H:12]2[CH2:16][N:15]([C:17](=[O:24])[CH2:18][CH2:19][S:20]C(=O)C)[C@H:14]([C:25]([OH:27])=[O:26])[CH2:13]2)=[CH:7][CH:6]=1)(=O)C.N>>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C@@H:12]2[CH2:16][N:15]([C:17](=[O:24])[CH2:18][CH2:19][SH:20])[C@H:14]([C:25]([OH:27])=[O:26])[CH2:13]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc(S[C@H]2C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C2)cc1
Agent: N
Product: O=C(O)[C@@H]1C[C@H](Sc2ccc(O)cc2)CN1C(=O)CCS

Procedure:
Hydrolysis of (cis)-4-(4-acetyloxyphenylthio)-1-[3-(acetylthio)-1-oxopropyl]-L-proline with an aqueous ammonia solution according to the procedure of Example 2 yields (cis)-4-(4-hydroxyphenylthio)-1-(3-mercapto-1-oxopropyl)-L-proline.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][N:4]=1.[CH2:15]=[O:16]>CC(C)=O>[OH:16][CH2:15][N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([C:2]([F:1])([F:13])[F:14])=[N:4]1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: C=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(CO)nc1C(F)(F)F
Temperature: 150 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
The mixture of 2.08 g of 3-(trifluoromethyl)-4-ethyoxycarbonyl-1H-pyrazole and 0.66 g of paraformaldehyde was stirred at 150° C. for 4 hours. After the reaction mixture was cooled to room temperature, acetone was added. After the mixture was filtered, the filtrate was concentrated under reduced pressure to obtain 2.23 g of 1-(hydroxymethyl)-3-(trifluoromethyl)-4-ethoxycarbonyl-1H-pyrazole.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH:4]([OH:14])[CH2:5][N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[N:7]1>CCO.[OH-].[OH-].[Pd+2]>[NH2:11][C:9]1[CH:8]=[N:7][N:6]([CH2:5][CH:4]([OH:14])[CH2:3][N:2]([CH3:1])[CH3:15])[CH:10]=1
Reactant: CN(C)CC(O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CC(O)Cn1cc(N)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
Pd(OH)2 (25 mg) was added to a solution of 1-(dimethylamino)-3-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (526 mg, 2.46 mmol) in EtOH (3 mL) and the mixture was stirred at rt under H2 balloon for 5 hrs. The mixture was filtered through Celite. The filtrate was concentrated to give the crude title compound as an orange oil (452 mg, 100%) which was used crude in subsequent steps. m/z (APCI+) for C8H16N4O 185.10 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH2:14][C@H:15]([OH:16])[CH3:17])[CH:8]=[CH:7]2
Reactant: C[C@@H]1CO1
Reactant: Fc1cc2cc[nH]c2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C[C@@H](O)Cn1ccc2cc(F)c(F)cc21
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A suspension of 0.12 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 5,6-difluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.46 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 60 hours and subsequently treated with water. The mixture was diluted with ether, washed twice with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 35 g of silica gel with toluene-ethyl acetate (19:1). 0.46 g (66.5%) of (R)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol was obtained as yellowish crystals with m.p. 114°-116°.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=2)[N:7]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C=O)C>[O:19]1[CH2:20][CH2:21][N:16]([CH2:2][C:3]2[O:4][C:5]3[C:6](=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:10][CH:11]=3)[N:7]=2)[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cccc2oc(CCl)nc12
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2oc(CN3CCOCC3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.2 %

Procedure:
A mixture of the product from Step B (281 mg, 1.24 mmol) and morpholine (2.0 mL, 23 mmol) in DMF (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate (10 mL). The formed precipitate was filtered off and mother liquor was concentrated under reduced pressure to afford methyl 2-(morpholinomethyl)benzoxazole-4-carboxylate (333 mg, 97%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J=9.0, 1.0 Hz, 1H), 7.74 (dd, J=9.0, 1.0 Hz, 1H), 6.40 (t, J=7.8 Hz, 1H), 4.02 (s, 2H), 3.97 (s, 3H), 3.78-3.74 (m, 4H), 2.69-2.65 (m, 4H); MS (ESI+) m/z 277 (M+H).
Reaction SMILES: CC(C)[N:3]=[C:4]=[N:5]C(C)C.CCN=C=NCCCN(C)C.[CH:21]1[CH:22]=[CH:23][C:24]2[N:29]([OH:30])[N:28]=[N:27][C:25]=2[CH:26]=1>CN(C=O)C>[NH:3]=[C:4]=[NH:5].[CH:21]1[CH:22]=[CH:23][C:24]2[N:29]([OH:30])[N:28]=[N:27][C:25]=2[CH:26]=1
Reactant: CC(C)N=C=NC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N=C=N
Temperature: 25 °C

Procedure:
To a suspension of compound AE or AM′ (1.0 equiv.) in DMF, DIC (1.5 equiv.) or EDCI (1.5 equiv.), HOBt (1.5 equiv.) and the selected amine (1.5-5.0 equiv.) were added. The mixture was stirred at R.T. for 12-72 Hrs or heated through microwave irradiation for 5 min at 150° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:20])/[C:17]([OH:19])=[O:18])=[C:11]([F:21])[CH:10]=1)=[O:7].[H][H]>O1CCCC1.CO.[C].[Pd]>[CH3:28][Si:25]([CH3:26])([CH3:27])[C:23]1[CH:22]=[C:5]([CH:4]=[C:3]([Si:2]([CH3:1])([CH3:30])[CH3:29])[CH:24]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[C:11]([F:21])[CH:10]=1)=[O:7]
Reactant: C/C(=C\c1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1F)C(=O)O
Yield: 94 %

Procedure:
Compound 14 (214 mg) was dissolved in tetrahydrofuran (4.0 ml) and methanol (4.0 ml), and a 10% palladium carbon catalyst (70.0 mg) was added thereto. The obtained mixture was stirred at room temperature in a hydrogen atmosphere for 6 hours. The catalyst was removed by Cerite filtration, and the solvent was distilled off from the filtrate under reduced pressure. As a result, Compound 16 (202 mg, 94%) was obtained as an opalescent solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14].S(Cl)(Cl)=O>CN(C)C=O>[CH3:15][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:13])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:14]
Reactant: CC1(C)C(=O)Nc2cc(C(=O)O)ccc21
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)Nc2cc(C(=O)Nc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8 g. 2,3-Dihydro-3,3-dimethyl-2-oxo-(1H)-indole-6-carboxylic acid and 1 drop of dimethylformamide were heated in 50 ml. thionyl chloride for 1 hour to the boil under reflux, the substance thereby going into solution. The thionyl chloride was removed under vacuum, the residue was suspended in dichloromethane and a solution of 1.6 ml. aniline and 2.7 ml. triethylamine in 30 ml. dichloromethane added dropwise thereto at an internal temperature of 15° C. The reaction mixture was stirred for 15 minutes at ambient temperature, the solvent was removed in a vacuum and the residue was digested with water, filtered off with suction and recrystallised from ethyl acetate. There were obtained 2.8 g. (56% of theory) of the title compound; m.p. 205-206° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:18](OC)=[O:19])[CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[N:6]=[C:5]([CH2:18][OH:19])[CH:4]=1
Reactant: COC(=O)c1cc(OC)n(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)nn1-c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round-bottomed flask was charged with methyl 5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxylate 72 (5.20 g, 17 mmol) and 100 mL of THF. After being cooled to 0° C., lithium aluminum hydride (1.0 M solution in THF, 17 mL, 17 mmol) was added dropwise. After 1 h, the reaction was quenched with 0.5 mL of water, 0.5 mL of 1 M NaOH, and 1.5 mL of water (added in that order). The resulting precipitate was filtered and the filtrate was concentrated to give (5-methoxy-1-(4-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)methanol 73.