Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[OH-].[Na+].[ClH:5].Cl.[CH2:7]([N:10]([CH2:26][CH2:27][CH3:28])[CH2:11][CH2:12][C:13]1[C:18]([CH2:19][C:20](O)=[O:21])=[C:17]([N+:23]([O-])=O)[CH:16]=[CH:15][CH:14]=1)[CH2:8][CH3:9]>[Pd]>[CH3:9][CH2:8][CH2:7][N:10]([CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[NH:23][C:20](=[O:21])[CH2:19][C:18]=12)[CH2:26][CH2:27][CH3:28].[ClH:5]
Reactant: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1CC(=O)O
Agent: [Pd]
Agent: Cl
Agent: OO
Product: CCCN(CCC)CCc1cccc2c1CC(=O)N2

Procedure:
The process as shown above comprises conversion of 2-methyl-3-nitro phenyl acetic acid (II) with thionyl chloride to 2-Methyl-3-nitro-phenylacetyl chloride (III), which upon reaction with Di-n-propyl amine (DPA) gives 2-Methyl-3-nitro phenyl-N,N-di-n-propyl acetamide (IV) in syrup form. This intermediate (IV) is further reduced with Borane/THF and subsequent treatment with HCl/NaOH to give 2-Methyl-3-nitro phenyl ethyl-N,N-di-n-propyl amine (V). Further, compound (V) is treated with Na metal, Ethanol and diethyl oxalate to obtain Ethyl 6-(2-di-n-propylaminoethyl)-2-nitrophenyl pyruvate (VI), which is further treated with hydrogen peroxide , NaOH and HCl and converted to 6-(2-Di-n-propylaminoethyl)-2-nitro phenyl acetic acid hydrochloride (VII). This intermediate is reduced with palladium/carbon to give Ropinirole hydrochloride (Ia).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:17][N:18]3COCC[Si](C)(C)C)=[CH:14][CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.NC1C=C(C(C2C=C3C(C(C=CC4C=CC=CC=4)=NN3COCC[Si](C)(C)C)=CC=2)=C)C=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:29]=[CH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)=[CH2:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C=C(c1cccc([N+](=O)[O-])c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: C=C(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(c1cccc(N)c1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1

Procedure:
6-(1-(3-Nitrophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole was converted to 6-(1-(3-aminophenyl)-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as described in Example 11, step (iv) (140 mg, 95%): Rf sm 0.59, p 0.46 (ethyl acetate-hexane 4:6); FTIR (thin film) 3460, 3366, 3223, 3084, 3028, 2952, 2894, 2246, 1616, 1601, 1581, 1489, 1474, 1448, 1359.1303, 1249, 1217, 1076, 961, 909, 860, 836, 733, 692 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.96 (d, 1H, J=8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (m, 2H), 7.30 (m, 1H), 7.25 (m, 1H), 7.14 (m, 1H), 6.77 (m, 1H), 6.68 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 151.6, 147.7, 144.6, 143.9, 142.8, 142.4, 138.6, 132.8, 130.6, 130.2, 129.3, 128.0, 124.4, 123.6, 121.9, 121.5, 120.2, 116.4, 116.1, 110.8, 79.0, 67.9, 19.2, 0.0; HRMS (FAB) [M+Na]/z Calc'd 490.2291, found 490.2302.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:14]=[C:15]([NH:19][C:20](=[O:22])[CH3:21])[CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:23]N(C)C=O>>[CH3:23][N:19]([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([S:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=2)[CH:14]=1)[C:20](=[O:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)N(C)c1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
0.265 g (0.00657 mol) of NaH (60%) was suspended in 10 ml of dimethylformamide and treated while cooling with ice with a solution of 1.72 g (0.06 mol) of N-[3-(4-nitrophenylsulphanyl)-phenyl]-acetamide in 20 ml of dimethylformamide. After a few minutes the mixture was left to warm to room temperature and stirred for 1 hr. Then, 1.1 ml (0.0179 mol) of Mel were added slowly. The mixture was stirred at room temperature for 18 hrs., the solvent was thereafter removed and the residue was partitioned in water and ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:1. There were obtained 1.51 g (83%) of N-methyl-N-[3-(4-nitrophenylsulphanyl)-phenyl]-acetamide as yellow crystals; m.p.: 66-68° C.
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[S-:8][C:9]#[N:10].[K+].CN(C)C=O.C(OCC)C>O>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][S:8][C:9]#[N:10]
Reactant: N#C[S-]
Reactant: CC(C)(CO)CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(CO)CSC#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A mixture of 16.7 g of 3-bromo-2,2-dimethyl-1-propanol, 14.6 g of potassium thiocyanate and 60 ml of dimethylformamide was stirred for 4 hours at 130°- 140° C. The reaction solution was cooled to room temperature (hereinafter means "5°-20° C."), to which a mixture of 200 ml of diethyl ether and 200 ml of water was added. The ethereal layer was collected. The aqueous layer was extracted with 150 ml of diethyl ether. The combined ethereal layers were washed with a saturated saline, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was distilled under reduced pressure to obtain 12.4 g of 3-hydroxy-2,2-dimethyl-1-propylthiocyanate.
Reaction SMILES: Cl.COC1C=C2C(=CC=1)C=C(C([NH2:16])C)C=C2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:17](=[NH:16])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc2cc(C(C)N)ccc2c1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=N)cc1
Reaction time: 15 h
Yield: 230.8 %

Procedure:
To a solution of the amine 2.1 (2.51 g, 12.5 mmol) in 10 mL methanol were added p-anisaldehyde (1.5 mL, 12.5 mmol) and anhydrous sodium carbonate (1.3 g, 12.5 mmol). The mixture was stirred for 15 hours and was filtered through celite and concentrated to give 3.9 g of the corresponding p-anisaldehyde imine 2.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OCCC)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1C=CC=C[CH:3]=1>C(O)C.[Pd]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[CH2:2][CH3:3]
Reactant: CCCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCOC(=O)N1CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 19.3 g piperazine-1,4-dicarboxylic acid propyl ester benzyl ester in 200 ml ethanol were added 2.0 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 3 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was used in the subsequent reaction. Yield: 10.5 g.
Reaction SMILES: [N:1]1([C:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(Cl)Cl.C([BH3-])#N.C([N+](CCCC)(CCCC)CCCC)CCC>C([O-])([O-])=O.[Na+].[Na+]>[N:1]1([CH:6]2[CH2:7][CH2:8][N:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC(N3CCCC3)CC2)cc1

Procedure:
A solution of 2 g (0.0079 mol) of the compound of (C), 5 ml of 4.66M HCl (in isopropyl alcohol), 40 ml of methylene chloride and 4.46 g of tetrabutylammonium cyanoborohydride is stirred at ambient temperature overnight. The solution is diluted with sat. Na2CO3 solution and extracted with methylene chloride. The combined extracts are dried (Na2SO4) and concentrated in vacuo to give the title compound. An analytical sample is prepared by recrystallization from cyclohexane: m.p. 88°-89° C.; IR (KBr) 2200, 1600, and 820 cm-1 ; NMR (CDCl3) δ7.45 (d, 2H), 6.85 (d, 2H), 4.0-3.7 (m, 1H), 2.95-2.65 (m, 8H), and 2.15-1.65 (m, 8H); M.S. m/e 256 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[CH2:17][C:16]3[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=3)[N:10]([CH3:22])[C:9]2=[O:23])=[CH:5][CH:4]=1.[CH2:26]([N:28]([CH2:39][CH3:40])[CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:27]>ClCCl.CO.C(O)(=O)C.O>[CH2:39]([N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36][C:13]2[N:12]=[C:11]3[N:10]([CH3:22])[C:9](=[O:23])[N:8]([CH2:7][C:6]4[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:17][C:16]3=[CH:15][N:14]=2)=[CH:37][CH:38]=1)[CH3:40]
Reactant: COc1ccc(CN2Cc3cnc(S(C)(=O)=O)nc3N(C)C2=O)cc1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(C)C(=O)N(Cc2ccc(OC)cc2)C3)cc1
Temperature: 180 °C
Yield: 7.4 %

Procedure:
A mixture of 200 mg (0.55 mmol) of 3-(4-methoxybenzyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 300 mg (1.4 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 20 minutes and then cooled. The residue was subjected to column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue was evaporated with toluene. The residue was then dissolved in 40 ml of dichloromethane, washed with 40 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was triturated in hexane, filtered off and dried to give 20 mg (7%) of 7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydro-3-(4-methoxybenzyl)-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 112° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:21].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:21]
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@H](F)CC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C1C(Cc2c(Cl)cc(-c3cccnc3)cc2Cl)CCN1[C@H]1CC[C@H](F)CC1
Temperature: 25 °C

Procedure:
Heat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[trans-1-(4-fluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (Preparation 28) (0.346 g, 0.705 mmol), pyridine-3-boronic acid (0.173 g, 1.41 mmol), Pd(PPh3)4 (81 mg), 7 mL of 0.1 M Na2CO3 aq solution in 7 mL of dimethoxy ethane at 80° C. for 24 h. Cool the mixture to room temp and dilute with 20 mL of 1N NaHCO3. Dilute the mixture with 20 mL of EtOAc. Wash the organic layer with water, brine and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 421 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.CCCCCC>C(Cl)Cl.O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Maraviroc phosphate (6 gm) was dissolved in methylene chloride (50 ml) and water (40 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (4 ml) and stirred for 15 minutes. The layers were separated and the organic layer was dried with sodium sulfate and treated with carbon. The methylene chloride was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added hexane (40 ml) and stirred for 30 minutes at room temperature. The solid obtained was collected by filtration and dried to obtain 4.7 gm of maraviroc amorphous form (HPLC Purity: 99.95%).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29]3[N:30]=[CH:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[C:29]([O:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:39])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)[N:30]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (480 mg, 0.88 mmol) was dissolved in 15 mL of dichloromethane. The solution was cool to 0° C. followed by the addition of 5 nL of TFA. The resulting mixture was stirred at room temperature for 4 hrs. Solvent was removed by rotavap and the residue was washed with MeOH. Solid thus obtained was dried overnight under vacuum to afford 60 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 14% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1(N)[CH2:35][CH2:34]1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH:33]3[CH2:35][CH2:34]3)=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NC2CC2)C1
Yield: 78 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and cyclopropylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as a glass (64 mg, 78%); LCMS (method B): RT=3.70 min, M+H+=486.
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C@:13]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C@H:17]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[C@@H:16]([CH3:24])[O:15][CH2:14]1)=S)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>>[F:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@:13]12[CH2:14][O:15][C@H:16]([CH3:24])[C@H:17]1[C@@H:18]([C:19]([F:22])([F:21])[F:20])[O:23][C:10]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[N:12]2
Reactant: C[C@H]1OC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)[C@@H]1C(O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: C[C@H]1OC[C@]2(c3ccccc3F)N=C(NC(=O)c3ccccc3)O[C@H](C(F)(F)F)[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
1-Benzoyl-3-[(3S,4R,5R)-3-(2-fluoro-phenyl)-5-methyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-tetrahydro-furan-3-yl]-thiourea (Preparation Example 30-(5)) (300 mg, 0.65 mmol) was dissolved in pyridine (1.39 g, 17.61 mmol). The reaction mixture was cooled to 0° C. Triflic anhydride (250 mg, 0.88 mmol) was added drop wise over 30 min, keeping temperature below 10° C. After 1 h, the reaction was concentrated then HCl 1M (50 ml) was added followed by extraction with DCM (2×50 ml). The organic phase was dried on MgSO4 and concentrated. The resulting mixture was purified by flash chromatography (Hexane/EtOAc 10-50%). 278 mg (93% yield) of the title compound (85%) and its isomer (15%) were isolated as a mixture.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[CH:11]=1)=[O:9])=[O:5])C.C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC([O-])=O)C=2)=O)=CC=1)C(C)C>>[C:4]([CH2:6][CH2:7][C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:11]=1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCn1cc(C(=O)CCC(=O)OCC)c2ccccc21
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)[O-])c2ccccc12)c1ccc(CC(C)C)cc1
Product: O=C(O)CCCn1cc(C(=O)CCC(=O)O)c2ccccc21

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-(3-ethoxycarbonylpropionyl)-1-indolyl]butyrate obtained in Ex. 40 was used in place of 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-[3-(3-carboxy-propionyl)-1-indolyl]butyric acid as a powder.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[NH2:12][C:13]1[N:18]=[C:17](C(Cl)(Cl)Cl)[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1.Cl.[CH3:28][OH:29]>>[NH2:12][C:13]1[N:18]=[C:17]([O:29][CH3:28])[N:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Reactant: CO
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(N)nc(C(F)(F)F)n1
Temperature: 20 °C

Procedure:
2.7 g (18 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene were added at 22° C. to a solution of 5 g (18 mmol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine in 25 ml of methanol. The mixture was refluxed for 1 hour and, after cooling to 20° C., made weakly acid (pH=6) with 2 normal aqueous hydrochloric acid. Then most of the solvent was removed under reduced pressure, after which the solid was isolated in a conventional manner.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([F:24])([F:23])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1.C(O)(C(F)(F)F)=O>CCO.[OH-].[OH-].[Pd+2]>[NH2:8][CH2:9][C:10]([F:23])([F:24])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)CCCOCC(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCOCC(F)(F)CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a solution of tert-butyl 4-(3-(dibenzylamino)-2,2-difluoropropoxy)butanoate (120 mg, 0.29 mmol) in EtOH (1 mL) was added 50 mg Pd(OH)2 (10 mg, 20% on C) followed by the addition of TFA (25 μL). The reaction mixture was stirred at room temperature under H2 for 18 h. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to yield tert-butyl 4-(3-amino-2,2-difluoropropoxy)butanoate (50 mg, 72% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:29][CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(CN)cc1
Product: CCCCN1C(=O)C(NCc2ccc(OC)cc2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(4-methoxyphenyl)methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (CD3CN) δ 7.50-7.33 (m, 5H), 6.79-6.74 (m, 4H), 6.34-6.26 (m, 1H), 4.08 (d, J=6.7 Hz, 2H), 3.75 (s, 3H), 3.67 (t, J=7.2 Hz, 2H), 1.81-1.71 (m, 2H), 1.49-1.38 (m, 2H), 0.97 (t, J=7.5 Hz, 3H); Mass spectrum: M−H+ 399.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:32][OH:33].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:33][NH:32][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(-c4ccccc4)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.2 %

Procedure:
To a solution of compound 12j (125 mg, 0.281 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (194 mg, 2.80 mmol) and a freshly prepared solution of sodium methoxide in methanol (96 mg, 4.20 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13j (9 mg, yield 7.2%). HPLC: 97.51% (Rt=14.61 min).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:19][CH3:20])(=[O:18])[C:8]1[CH:17]=[CH:16][CH:15]=[C:10]([C:11]([O:13]C)=O)[CH:9]=1.Cl.[C:22](#[N:24])[CH3:23]>O>[C:22]([CH2:23][C:11]([C:10]1[CH:9]=[C:8]([CH:17]=[CH:16][CH:15]=1)[C:7]([O:19][CH3:20])=[O:18])=[O:13])#[N:24]
Reactant: CC#N
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COC(=O)c1cccc(C(=O)CC#N)c1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (6.4 g) was added to a solution of dimethyl isophthalate (10.0 g) in acetonitrile (90 ml) at ambient temperature and the mixture was stirred for 1 hour at 60°-64° C. The reaction mixture was added to a solution of conc. hydrochloric acid (4.7 ml) in water (150 ml) and extracted with ethyl acetate. The extract layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-(cyanoacetyl)benzoate (4.72 g).