Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH2:23][NH:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:34]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][N:24]([C:25]([O:27][CH:28]([CH3:29])[CH3:30])=[O:26])[CH3:34])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)OC(=O)NCc1ccc(OCc2ccccc2)cc1CCC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N(C)Cc1ccc(O)cc1CCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
To a solution of 3-[5-benzyloxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid tert-butyl ester (6.3 g, 0.015 mol) in DMF (100 mL) was added NaH (29.4 mmol, 60% oil dispersion). The reaction mixture was stirred at 0° C. for 15 min, treated with methyl iodide (4.18 g, 29.4 mmol), and stirred overnight under N2 at ambient temperature. The mixture was concentrated and triturated with hexanes (200 mL). The residue was diluted with EtOAc (200 mL), and the solution was washed with water (200 mL) and brine (200 mL), dried (Na2SO4), and concentrated to a yellow oil (5.2 g). The material was dissolved in EtOAc (100 mL), and 5% Pd/C (0.725 g) was added. The reaction mixture was shaken under a hydrogen atmosphere in a Parr apparatus at 60 psi overnight at 40° C. The mixture was filtered and concentrated to give the title compound (2.1 g). MS [ES] m/z 352 (M+H)+.
Reaction SMILES: C(OC([N:7]1[CH2:12][CH2:11][C:10]2[C:13]([C:27](=[O:29])[NH2:28])=[C:14]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[O:18])[S:15][C:9]=2[CH2:8]1)=O)C=C.N1CCOCC1>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[NH:16][C:14]2[S:15][C:9]3[CH2:8][NH:7][CH2:12][CH2:11][C:10]=3[C:13]=2[C:27]([NH2:28])=[O:29])=[CH:25][CH:24]=1
Reactant: C=CCOC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2

Procedure:
Starting material 9 (750 mg, 1.7 mmol) was dissolved under Nitrogen atmosphere in 10 ml DCM in a 2 necked flask and a solution of morpholine (3 ml, 34.5 mmol) in 34.5 ml DCM was added. The solution was stirred for 5 Min. then a solution of Tetrakis(triphenylphosphin)-palladium(0) (199 mg, 0.2 mmol) in 17.2 ml DCM was added. After about 8 Min a brown suspension was formed. The reaction was stirred at ambient temperature for another 40 Min. The solvent was then reduced and product 5 was thereby isolated in two fractions: very pure as white crystals (246 mg, 0.7 mmol, 41%) and with 56% content in a brown solid (250 mg, 56% Gehalt an 5, 0.4 mmol), which contained side products as well but could be purified by prep. HPLC (Method 2). The pure product fractions were merged, the solvent reduced and the product lyophilized.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)[CH3:2].[CH3:15][NH:16][NH2:17]>C(O)(=O)C>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C:4]1[C:12]([CH3:13])=[N:17][N:16]([CH3:15])[C:1]=1[CH3:2])[CH3:11]
Reactant: CCOC(=O)CCC(C(C)=O)C(C)=O
Reactant: CNN
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C)nn(C)c1C
Yield: 92.8 %

Procedure:
Dissolve ethyl 4-acetyl-5-oxohexanoate (2.00 g, 9.99 mmol) in acetic acid (21 mL). Add methyl hydrazine (589 μL, 10.99 mmol) and stir at room temperature for 18 hr. Concentrate and dissolve residue in ethyl acetate. Wash ethyl acetate layer with saturated aqueous sodium bicarbonate solution. Extract aqueous layer twice with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 100% ethyl acetate:hexanes) to give 3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-propionic acid ethyl ester (1.95 g, 93%). MS (ES): m/z=211 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34]([CH:39]=O)=[CH:33]3)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:39][C:34]2[NH:35][C:36]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:38][CH:37]=3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:12]=[N:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Br.C([OH:17])C>>[C:7]1(=[O:17])[C:6]2[C:5](=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][NH:8]1
Reactant: CN(C)/C=C/c1cnccc1C#N
Reactant: CCO
Agent: Br
Product: O=c1[nH]ccc2cnccc12
Temperature: 25 °C

Procedure:
To a suspension of (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (5 g, 28.9 mmol) in ethanol (50 mL) was added 49 mL of HBr (48% in water) dropwise over 20 minutes. The mixture was heated to reflux overnight for 19 h, and cooled to rt. Upon cooling, fine yellow crystals started to form. The mixture was cooled in the refrigerator for 1.5 h. The crystals were collected by filtration and were washed with ether. To the yellow solid was carefully added sat. aq. NaHCO3 until gas evolution ceased. The off-white solid that formed was collected by filtration and was washed with water to give 1.83 g of the expected product. The mother liquors from both filtrations were combined and were concentrated under reduced pressure. The residue was neutralized with sat. aq. NaHCO3, and the solvent removed under reduced pressure. The residue was diluted with 300 mL of dichloromethane and 300 mL of MeOH, and the mixture was warmed to reflux with a heat gun. The solids were removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 0-6.5% MeOH in dichloromethane gradient. The expected product, was isolated as an off-white solid (0.96 g) and the two lots were combined to yield 2,6-naphthyridin-1(2H)-one (2.79 g, 19.1 mmol, 66% yield). LC/MS: m/z 147.04 (M+H)+, 1.407 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H) 9.07 (s, 1H) 8.62 (d, J=5.49 Hz, 1H) 7.98 (d, J=5.49 Hz, 1H) 7.33 (d, J=7.02 Hz, 1H) 6.67 (d, J=7.02 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1.P([O-])(O)(O)=[O:34].[Na+].Cl[O-].[Na+].OO>C(#N)C.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]([OH:34])=[O:12])=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: COc1c(C)c(Cc2ccc(C=O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reactant: O=P([O-])(O)O
Agent: OO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2ccc(C(=O)O)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Yield: 101.5 %

Procedure:
To a solution of 4-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (735 mg, 1.69 mmol) in acetonitrile (5 ml) were added an aqueous solution (2 ml) of sodium dihydrogen phosphate (157 mg, 1.31 mmol), an aqueous solution (7 ml) of sodium hypochlorite (795 mg, 80%, 7.07 mmol) and an aqueous hydrogen peroxide (0.5 ml, 30%) and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium hydrosulfite (Na2S2O4) and a saturated saline, dried and concentrated to give the title compound (603 mg, 1.33 mmol, 79%).
Reaction SMILES: [C:1]1([CH:7]2[C:16]3[C:11]4=[C:12]([CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:19][CH2:20][N:10]4[CH2:9][CH2:8]2)[CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[C:21]1([CH:18]2[C:12]3[C:11]4=[C:16]([CH:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:8][CH2:9][N:10]4[CH2:20][CH2:19]2)[CH:15]=[C:14]([NH:17][C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:13]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cc2c3c(c1)C(c1ccccc1)CCN3CCC2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
To a solution 1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-amine (Intermediate 4), (106 mg, 0.31 mmol) in dichloromethane (10 mL) was added triethyl amine (0.130 mL, 0.933 mmol) followed by dimethylcarbamic chloride (0.043 mL, 0.46 mmol), under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give 3-(1,7-diphenyl-1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)-1,1-dimethylurea, (405), (63 mg 49%). 1H NMR (300 MHz, CDCl3) ppm 2.01-2.16 (m, 2H) 2.20-2.37 (m, 2H) 2.85 (s, 6H) 3.00-3.15 (m, 4H) 4.12-4.25 (m, 2H) 5.78 (s, 1H) 6.62 (s, 2H) 7.10-7.22 (m, 5H) 7.23-7.34 (m, 5H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>S(Cl)(Cl)=O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCN1CCCC1
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Solvent: O=S(Cl)Cl
Product: O=C(OCCN1CCCC1)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1

Procedure:
Treatment of 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1 g, Example 33b) with thionyl chloride (10 ml) followed by 1-(2-hydroxyethyl) pyrrolidine (0.43 ml) as described in Example 33c, gave 2-(1-pyrrolidinyl)ethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.7 g). δ (360 MHz, DMSOd6) 1.70 (4H, bs, pyrrolidine-3,4-H), 2.60 (4H, bs, pyrrolidine-2.5-H), 2.88 (2H, t, CH2N), 4.48 (2H, t, CO2CH2), 5.50 (2H, s, OCH2), 7.38 (3H, m, m,p-ArH), 7.58 (2H, d, o-ArH), 7.71 (1H, s, 3-H), 7.86 (1H, d, 6-H) and 8.13 (1H, d, 8-H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([S:11]([OH:13])=[O:12])[CH:10]=1.[OH-].[Na+].[CH:26]1([CH2:29]Br)[CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([S:11]([CH2:29][CH:26]2[CH2:28][CH2:27]2)(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)O
Reactant: BrCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)CC1CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 14 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfinic acid (1.0 g, 2.64 mmol) in ethanol was added NaOH (116 mg, 2.89 mmol) and cyclopropylmethyl bromide (1.40 mL, 14.5 mmol). The resulting mixture was stirred at 70° C. for 6 h, then at 50° C. for 20 h and concentrated to dryness. The residue was dissolved in 1 N HCl (40 mL) and extracted with EtOAc (4×40 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (CH2Cl2: Hex=4:1) to give the title compound of Step C (160 mg) as a solid. MS (APCl−) Caic.: 431.0, Found: 430.2 (M−1).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([N:7](CC2C=CC(OC)=CC=2)[S:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[S:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[N:6]=[C:5]([NH:7][S:8]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)=[CH:16][N:17]3[CH3:20])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[S:4][N:3]=1
Reactant: COc1ccc(CN(c2nc(Br)ns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3nc(Br)ns3)ccc12
Reaction time: 2.5 h
Yield: 84.6 %

Procedure:
A 10-mL round-bottom flask was charged with N-(3-bromo-1,2,4-thiadiazol-5-yl)-N-(4-methoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (28 mg, 0.039 mmol), DCM (1 mL), and trifluoroacetic acid (60.1 μl, 0.780 mmol). The flask was sealed, and the mixture was stirred for 2.5 h. An additional portion of TFA (0.15 mL) was added, and the resulting mixture was stirred for 48 h. The volatiles were removed in vacuo, and the residue was concentrated again from DCM. The crude product was purified by chromatography on silica gel (5 to 10% MeOH/DCM) to give N-(3-bromo-1,2,4-thiadiazol-5-yl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonamide (19.91 mg, 0.033 mmol, 85% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.94-7.83 (m, 3 H), 7.75 (s, 1 H), 7.55 (d, J=8.5 Hz, 1 H), 7.46-7.35 (m, 2 H), 7.05 (s, 1 H), 6.36 (d, J=1.9 Hz, 1 H), 3.78 (s, 3 H), 3.21 (s, 3 H). m/z (ESI) 597.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Cl:3][C:4]1[N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
According to Scheme A, a mixture of NaH (60% dispersion in oil, 0.40 g, 9.8 mmol) and THF (10 mL) was cooled to 0° C., then solid 2-chlorobenzoimidazole (1.0 g, 6.5 mmol) was added portion wise over 10 min. The resulting mixture was stirred at 0° C. for 1 h, then 2-(trimethylsilyl)-ethoxymethyl chloride (1.5 mL, 8.5 mmol) was added. The reaction mixture was allowed to warm to 23° C. and was stirred 16 h. The mixture was carefully poured over ice (200 g) and then was extracted with Et2O (3×100 mL). The combined organic extracts were dried, filtered, and concentrated. The residue was purified (FCC) (1:99 to 15:85 EtOAc/hexanes) to yield the titled compound, which has been previously described (WO 2005/012296, Janssen Pharmaceutica N.V., Example 7).
Reaction SMILES: C(OC([N:8]1[C@@H:13]([C@@H:14]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@H:10]([O:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)[CH2:9]1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>ClCCl>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH2:30]([O:29][C@H:14]([C@H:13]1[CH2:12][O:11][C@H:10]([O:37][CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:9][NH:8]1)[C@@H:15]([NH:25][C:26](=[O:28])[CH3:27])[CH2:16][C:17]1[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1CO[C@H](OCCCC2CCCC2)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](OCc1ccccc1)[C@H]1CO[C@H](OCCCC2CCCC2)CN1
Reaction time: 0.33 h

Procedure:
Dissolve (2S,5R)-5-[(1S,2S)-2-Acetylamino-1-benzyloxy-3-(3,5-difluorophenyl)-propyl]-2-(3-cyclopentylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (67 mg, 0.106 mmol) in neat trifluoroacetic acid under nitrogen. After 20 min, dilute the reaction mixture with dichloromethane and concentrate it on the rotary evaporator four times, then dilute with benzene and concentrate again. Dry the residue under vacuum to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([CH:43]3[CH2:45][CH2:44]3)=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][C:40]([CH:43]3[CH2:44][CH2:45]3)=[CH:41][CH:42]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (152 mg, 0.5 mmol) and 3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K21) (169 mg, 0.5 mmol) according to the general procedure M. Obtained as a light yellow foam (211 mg, 74%).
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6]Cl.[N-:12]=[N+:13]=[N-:14].[Na+].[N-]=[N+]=[N-]>CO>[CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][N:12]=[N+:13]=[N-:14]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: CO[Si](CCCN=[N+]=[N-])(OC)OC

Procedure:
To a 2 liter, 3-necked round bottom glass flask fitted with a stirrer, heating mantle, reflux condenser, and nitrogen inlet source was charged 99 grams (0.5 mole) of a 3-trimethoxysilylpropylchloride, 112 grams (1.72 moles) sodium azide and 1 liter of methanol. The mixture was stirred at reflux temperature for 11 days, cooled to about 10 C. in a wet-ice bath and filtered. The filtrate was concentrated under vacuum on a steam bath. The semi-solid sludge was treated with 0.2 liter n-heptane, filtered and again concentrated under vacuum on a warm water bath. Continued distillation gave a 62 mole % yield of product (74 C./63 mm) comprised of 92 wt.% azide product and 8 wt.% 3-trimethoxysilylpropylchloride.
Reaction SMILES: C[O-].[Na+].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13].C(O)(=O)C>CN(C)C=O>[CH:12]([C:11]1[O:15][CH:5]=[N:4][C:6]=1[C:7]([O:9][CH3:10])=[O:8])([CH3:14])[CH3:13]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CC(C)C(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1C(C)C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
13.7 g of sodium methoxide are dissolved in 200 ml of dimethylformamide, and 19.4 g of methyl α-isocyanoacetate are added dropwise thereto at -50° C. to -40° C. The mixture is stirred at the same temperature for 30 minutes. 25 g of isobutyryl chloride are gradually added to the mixture at -50° C. to -40° C., and said mixture is stirred at the same temperature for 2 hours. After the reaction, the mixture is adjusted to pH 3-4 with acetic acid and then condensed under reduced pressure to remove solvent. The residue is extracted with ethyl acetate and the extract is washed with aqueous sodium bicarbonate solution and water, successively. The extract is then dried and condensed under reduced pressure to remove solvent. 23.1 g of 5-isopropyl-4-methoxycarbonyloxazole are obtained. Yield: 70.0%.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[H-].[Na+].I[CH3:18]>CN(C=O)C>[CH3:18][O:1][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CI
Reactant: COC(=O)c1cc2c(cc1O)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(cc1OC)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 107.7 %

Procedure:
A mixture of methyl 6-hydroxy-1,3-benzodioxole-5-carboxylate (2.7 g, 14 mmol), sodium hydride (456 mg, 19 mmol, 760 mg of a 60% dispersion in mineral oil), iodomethane (1.9 g, 13 mmol) and DMF (approximately 35 mL) was stirred 2 hours. The mixture was poured into ice-water and the mixture was extracted with diethyl ether (2×). The combined extracts were washed with water (3×) and brine (1×) and concentrated to give methyl 6-methoxy-1,3-benzodioxole-5-carboxylate (3 g, 14 mmol), m.p. 74°-75° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[SH:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:12]=1[S:18][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9]
Reactant: CN1CCCC1CCCl
Reactant: Oc1ccc(S)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCSc1ccc(O)cc1Cl

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (2.85 g, 19.29 mmole), 2-chloro-4-hydroxythiophenol (3.1 g, 19.29 mmole), potassium carbonate (26.7 g, 192.9 mmole) and DMF (30 mL) were combined, yielding 3.2 g (11.77 mmole, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Br)[C:14]#[CH:15]>C(O)(C)C>[CH2:15]([O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:8])[C:14]#[CH:13]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C#CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#CCOC(=O)c1ccc(O)cc1
Yield: 62.9 %

Procedure:
p-Hydroxybenzoic acid (0.724 mole) and sodium hydroxide (0.724 mole) were dissolved in 50% isopropyl alcohol (400 ml). Propargyl bromide (0.724 mole) was added and the solution was heated to reflux for 6 hours. The solution was then cooled and the isopropyl alcohol was removed under vacuum. The residue was taken up in methylene chloride (200 ml), washed with water (200 ml), aturated sodium bicarbonate, saline and dried over magnesium sulfate. Removal of the solvent yielded crude product, which was recrystallized, from CCI4 to give pure propargylparaben. (62.9% yield) m.p. 107-108° C.
Reaction SMILES: [Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26].[I:27]N1C(=O)CCC1=O.N.ClCCl>FC(F)(F)C(O)=O>[Br:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[C:13]([I:27])[CH:14]=2)[CH2:9][C@H:8]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:7][N:6]1[CH3:26]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Reactant: O=C1CCC(=O)N1I
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(I)cc4[nH]c(Br)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
42 mg of 3-(2-bromo-6-methyl-8alpha-ergolinyl)-1,1-diethylurea (0.1 mmol) is dissolved in 2 ml of trifluoroacetic acid and mixed with 22 mg of N-iodosuccinimide (0.1 mmol). After 15 minutes of stirring at room temperature, ice is added, it is made alkaline with ammonia, and shaken out with dichloromethane. The organic phases are dried and concentrated by evaporation, the residue is chromatographed. The pure substance crystallizes from dichloromethane, yield 9 mg (16% of theory).