Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:34])C=CC=CC=1>ClCCl.CO>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:19](=[O:20])[N:18]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:11]2[N:12]=[C:13]([S:16]([CH3:17])=[O:34])[N:14]=[CH:15][C:10]=2[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(NC(=O)OC(C)(C)C)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88.6 %

Procedure:
(8-Cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester (1.3 g, 3.45 mmol, prepared according to Example 8) was added to 50:50 dichloromethane/methanol (12 ml) followed by 2-benzenesulfonyl-3-phenyl-oxaziridine (1.08 g, 4.14 mmol). The mixture was stirred at 25° C. for 3.5 hours, evaporated to an oil and eluted through silica gel with chloroform. Fractions containing the product were evaporated to yield (8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-carbamic acid tert-butyl ester as a solid (1.2 g, 89%). MS (APCI); M++1: Calc'd, 393.15, Found 393.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:7]=[C:6]([CH2:11][O:12][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: COCc1cc(O)cc(O)c1C=O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: COCc1cc(OC2CCCCO2)cc(O)c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
To a mixture of 2,4-dihydroxy-6-methoxymethyl-benzaldehyde (2.62 g, 14.45 mmol) in dichloromethane (50 mL) was added 3,4-dihydro-2H-pyran (2.42 g mL, 28.90 mmol) and pyridium p-toluenesulfonic acid (0.050 g) at room temperature. The resulting mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give 2-hydroxy-6-methoxymethyl-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (3.06 g, 80%). 1H NMR (400 MHz, CDCl3) δ 12.30 (s, 1H), 10.10 (s, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 5.47 (s, 1H), 4.60 (s, 2H), 3.80 (m, 1H), 3.60 (m, 1H), 3.40 (s, 3H), 2.00-1.50 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][C:23]=1[C:24]([NH2:26])=[O:25]>>[C:1]([O:5][C:6](=[O:17])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:18][C:19]2[S:20][C:21]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:22][C:23]=2[C:24]([NH2:26])=[O:25])[N:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: CN(Cc1cccc(Br)n1)C(=O)OC(C)(C)C
Product: CN(Cc1cccc(Nc2sc(-c3ccc(F)cc3)cc2C(N)=O)n1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure in Example 1 using tert-butyl[(6-bromopyridin-2-yl)methyl]methylcarbamate (90.0 mg, 0.299 mmol) and 2-amino-5-(4-fluorophenyl)thiophene-3-carboxamide (78.0 mg, 0.329 mmol) as the starting materials.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)[N:3]=1.C1C(=O)N([Br:33])C(=O)C1.OS([O-])=O.[Na+]>C(#N)C.C(OCC)(=O)C>[Br:33][C:10]1[C:2]([Cl:1])=[N:3][C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:17]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1ccc(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)c1cc(Br)c(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reaction time: 8 h
Yield: 38.6 %

Procedure:
A suspension of 6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (500 mg, 1.385 mmol) and NBS (250 mg, 1.4 mmol) in acetonitrile (10 mL) was stirred at overnight. The reaction mixture was treated with 1M NaHSO3 and stirred at rt for 2 h. Next, the reaction mixture was diluted with ethyl acetate and the precipitate filtered to give a solid. The organic layer of the filtrate was separated and concentrated to an additional amount of solid. The above solids were combined and triturated with 250 mL of MeOH/CH2Cl2 (˜1:1 ratio) to give 235 mg of 5-bromo-6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide as a grey solid. LCMS: (M+H)+=338.80, 440.83, 442.87 (Br, Cl pattern). 1H NMR (400 MHz, methanol-d3-MIX) δ ppm 8.38 (1H, s), 7.77 (2H, d, J=8.35 Hz), 7.42 (2H, d, J=8.79 Hz), 3.69 (8H, br. s.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=3)=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)cc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
(RS)-2-(4-Amino-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg, CAS 1002726-96-6), 2,5-dichloropyridine (31.9 mg, CAS 16110-09-1) and cesium carbonate (105 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.48 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.69 mg) were then added. The reaction mixture was then capped and stirred at 100° C. overnight. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 70% EtOAc in hexanes) to afford (RS)-2-[4-(5-chloro-pyridin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (52 mg, 62%) as a yellow amorphous solid. MS (ISP): 392.0 ([{37Cl}M+H]+), 390.1 ([{35Cl}M+H]+), 336.4 ([{37Cl}M+H—C4H8]+), 334.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:23]=O.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[ClH:32]>C(O)C>[ClH:32].[ClH:32].[ClH:32].[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[S:11][CH:12]=2)=[CH:4][C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH3:23])[CH2:28][CH2:27]1
Reactant: C=O
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2nc(-c3ccc(O)cc3)cs2)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2nc(-c3ccc(O)c(CN4CCN(C)CC4)c3)cs2)cc1OC

Procedure:
In 25 ml of ethanol were suspended 0.5 g of 4-(4-hydroxyphenyl)-2-(3,4-dimethoxyphenyl)thiazole, 1 g of paraformaldehyde and 0.5 g of N-methylpiperazine. The suspension was refluxed for 8 hours with heating. The reaction mixture was subjected to distillation under reduced pressure to remove the solvent. The residue was purified by silica get column chromatography (eluent: dichloromethane/methanol=49/1 by v/v) and dissolved in 10 ml of ethanol. Thereto was added 0.5 ml of ethanol saturated with hydrogen chloride gas, and the mixture was allowed to stand. The resulting crystals were collected by filtration, dried and recrystallized from ethanol to obtain 0.2 g of 4-[4-hydroxy-3-(4-methyl-1-piperazinylmethyl)phenyl]-2-(3,4-dimethoxyphenyl)thiazole trihydrochloride.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:19]([CH2:23]Br)[C:20]([NH2:22])=[O:21].C(N(CC)CC)C.[OH-].[Na+]>C(OCC)C.CN(C)C=O>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:19]([C:20]([NH2:22])=[O:21])[CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: NC(=O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Temperature: 110 °C

Procedure:
To dimethylformamide (300 mL) add N-phenyl-N'-phenylmethyl-1,2-ethanediamine (83 g, 0.37 mol), 2,3-dibromopropanamide (90 g, 0.39 mol) and triethylamine (41 g, 0.40 mol). Heat the resulting mixture at 110° C. and follow the progress of the reaction by thin-layer chromatography. Upon completion of the reaction add 1N NaOH until basic and add ethyl ether. Filter the precipitate that forms and recrystallize from 2-propanol to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][C@@:11]1([NH:30]C(=O)OC(C)(C)C)[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.CCCCCCC>ClCCl>[NH2:30][C@:11]1([CH2:10][CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=2)[CH2:12]1
Reactant: CCCCCCCCc1ccc([C@H]2CC[C@@](CCP(=O)(OCC)OCC)(NC(=O)OC(C)(C)C)C2)cc1
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCc1ccc([C@H]2CC[C@](N)(CCP(=O)(OCC)OCC)C2)cc1
Reaction time: 1 h
Yield: 48.4 %

Procedure:
Tert-butyl (1R,3S)-1-(2-(diethoxyphosphoryl)ethyl)-3-(4-octylphenyl)cyclopentylcarbamate (0.2 g, 0.372 mmol) was dissolved in dichloromethane (1.860 ml) in a sealed vial to give a colorless solution. TFA (1.860 ml) was added and the reaction stirred for about 1 h. Solvents were removed under reduced pressure. Methylene chloride (25 mL) and saturated sodium bicarbonate (25 mL) were added and the layers separated and extracted with methylene chloride (2×10 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to a yellow oil. The oil was dissolve in ether (15 mL). 1 M HCl in dioxane (3 mL) was added. Solvents were removed under reduced pressure. The solid was redissolved in water and lyophilized. The resulting white/tan solid was suspended in ether and the resulting solid was collected by vacuum filtration and washed with ether then heptane to provide diethyl 2-((1R,3S)-1-amino-3-(4-octylphenyl)cyclopentyl)ethylphosphonate (0.0787 g, 0.180 mmol, 48.4% yield) as a white solid on drying under vacuum: LCMS (method a) Rt=3.46 min.; MS m/z: 438.48 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([NH:14][C:15](=[O:30])[CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH:28]=[CH:27][N:26]=[N:25]3)[CH:19]=2)=[CH:12][C:11]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[C:10]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:11]1[C:10]([O:38][CH2:39][C:40]([F:41])([F:42])[F:43])=[CH:9][C:8]2[N:7]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH:19]=3)[CH2:16][C:15](=[O:30])[NH:14][C:13]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2cc(OCC(F)(F)F)c(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from [2′-fluoro-5-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example M24) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an orange solid (45 mg).
Reaction SMILES: C(N)(C)(C)C.[CH3:6][C@@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9].C(=O)=O.C1(/C(=C\C2C=CC=CC=2)/C(O)=O)C=CC=CC=1>CO>[CH3:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: C[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)/C(=C/c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: CC(C)(C)N
Solvent: CO
Product: C[C@H](Cc1ccccc1)C(=O)O

Procedure:
(S)-2-Methyl-3-phenylpropionic acid tert-butylamine salt, reaction time 40 minutes, conversion 100%, ee 96.5% (SFC, 2× Chiralpak AD-H columns, 10% methanol, 3000 psi CO2, 35° C., flow rate 3 ml/minute, retention times R 7.1 minutes, S 7.7 minutes, (E)-phenylcinnamic acid 12 minutes). The free acid was liberated by partitioning between dichloromethane and 2M HCl. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated to give (R)-2-Methyl-3-phenylpropionic acid as a pale yellow solid. [α]D20+98.6, c=2.03, CHCl3. [α]D20+100.6, c=0.54, acetone. [α]D20+103.5 (c=1.00, MeOH). Lit. (M. B. Watson and G. W. Youngson, J. Chem. Soc. C, 1968, 258-261; +140.8, c=2.04, CHCl3). 1H NMR analysis of the (S)-methyl mandelate (E. Tyrell, M. W. H. Tang, G. A. Skinner and J. Fawcett, Tetrahedron, 1996, 52, 9841-9852) confirmed assignment of (S)-configuration.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H].[CH2:20]1[C@@H:28]2[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:22][NH:21]1>[C].[Pd]>[CH2:9]1[C@H:10]2[C@@H:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1.[CH3:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:20][NH2:21]
Reactant: c1ccc(CN2Cc3ccccc3C2)cc1
Reactant: [H][H]
Reactant: C1CC[C@H]2CNC[C@H]2C1
Agent: [Pd]
Agent: Cl
Product: C1CC[C@H]2CNC[C@@H]2C1
Product: CC1CCCCC1CN
Yield: 0.1 %
Yield: 0.7 %

Procedure:
In a 3-liter GL autoclave fitted with a electromagnetic stirrer are added 226.5 g of N-benzylisoindoline, 545 g of 7.2% hydrochloric acid aqueous solution (pH 4.0) and 26 g of 5% palladium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 130° C. After a 10 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 83.8%. In addition, 0.1% of trans-hexahydroisoindoline and 0.7% of 2-methylcyclohexylmethylamine is formed. After cooling the reacted solution, 240 g of 20% sodium hydroxide aqueous solution is added to neutralize, and it is extracted with toluene. After concentrating the organic phase, the residue is purified by distillation to give 99.7 g of cis-hexahydroisoindoline (yield 79.6%).
Reaction SMILES: ClCCl.Cl[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[CH2:23]([N:25]([CH2:38][CH3:39])[CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]1)[CH3:24]>C(#N)C>[CH2:38]([N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][N:28]([CH3:37])[CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6])[CH3:39]
Reactant: CCN(CC)CCN(C)CCC1CCCCN1
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Solvent: CC#N
Solvent: ClCCl
Product: CCN(CC)CCN(C)CCC1CCCCN1C(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 22 %

Procedure:
Prepared analogously to Example 4, but using dichloromethane instead of acetonitrile as solvent, from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[2-[[2-(diethylamino)ethyl]methylamino]ethyl]piperidine (b.p.0.3 mmHg 92°-95° C.) in a yield of 22% of theory. Colourless crystals, m.p. 131°-133° C. (acetonitrile).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[CH3:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[N:26]([CH3:25])[CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cn1ccnc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Product: Cn1ccnc1C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12l and 1-methylimidazole
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([SH:38])[CH2:21][CH2:22]CCCCCCCCCCCCCCC.BrCC[C:42](OC)=[O:43].C(OC)(=O)C=C.C[O-].[Na+]>>[CH2:1]([CH2:22][CH2:21][C:20]([O:43][CH3:42])=[S:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: COC(=O)CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: C=CC(=O)OC
Product: CCCCCCCCCCCCCCCCCCCCC(=S)OC

Procedure:
Instead of octadecyl bromide, there can also be used octadecyl mercaptan which is then reacted with methyl 3-bromopropionate or added on to methyl acrylate with sodium methylate catalysis. In both cases, methyl 3-octadecylthiopropionate is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:11][CH2:10][C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:12][NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[O:15])[CH2:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([CH2:12][NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[O:15])[CH2:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CC=C(COC(C)=O)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(COC(C)=O)CC1

Procedure:
A solution of 1-acetoxymethyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohex-1-ene (Example 200, 11.5 mg, 0.029 mmol) in 5 mL of EtOAc was shaken with Pd/C (5 mg, 10%) under 50 psi of hydrogen for 14 h. The mixture was filtered through silica gel, concentrated and purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 4.5/8.0 mL/min) to give the 2 isomers of the title compound
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[OH:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:41][CH2:42][NH:43]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][C:3]=1[O:20][CH2:41][CH2:42][NH2:43]
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cc2ccn(S(=O)(=O)c3ccccc3)c2cc1F
Temperature: 150 °C
Reaction time: 2 h
Yield: 59.8 %

Procedure:
To 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 28, 3.0 g, 10 mmol), 1,1′-azobis(N,N (3.5 g, 21 mmol), triphenylphosphine (5.4 g, 21 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (3.3 g, 21 mmol) and DCM (20 mL) were added. The mixture was heated at 150° C. for 20 minutes in a microwave heater. The reaction mixture was allowed to cool to room temperature and TFA (20 mL) was added. The reaction mixture was allowed to stir at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude material was filtered through a plug of silica gel using DCM as eluent. The solvent was removed under reduced pressure and the crude material was dissolved in ethyl acetate (10 mL) and the HCl salt of the title compound precipitated when 1 M HCl in diethylether (20 mL) was added. The solid was filtered off, dissolved in DCM (100 mL) and organic phase was washed with saturated aqueous NaHCO3 (40 mL) to give the title compound (2.0 g). MS m/z 335 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:26]CCl>S(Cl)(Cl)=O.CN(C)C=O>[Cl:26][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: OCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CCl)cc2)=NO1
Temperature: 0 °C

Procedure:
In a solution of 4.2 g of 5-(3,5-dichlorophenyl)-3-[4-(hydroxymethyl)phenyl]-5-trifluoromethyl-4,5-dihydro-isoxazole in 100 mL of dichloromethane, 1.2 mL of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heating for 3 hours. After the completion of the reaction, the reaction mixture was poured into 30 mL of ice water, the organic phase was collected, washed with water (50 mL×1) and saturated sodium hydrogen carbonate aqueous solution (30 mL×3), and thereafter dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluted with ethyl acetate-hexane (1:5) to obtain 4.1 g of the aimed product as pale yellow crystal.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([CH2:8][C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:11])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[OH2:33]>C(Cl)Cl>[C:15]([O:14][C:13]([NH:12][C@@H:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:20])([F:1])[CH2:3][CH2:4]1)[CH2:10][CH2:28][S:29]([OH:31])(=[O:33])=[O:30])=[O:19])([CH3:18])([CH3:17])[CH3:16].[CH3:28][S:29]([OH:31])(=[O:11])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(F)(F)CC1
Reactant: O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCS(=O)(=O)O)CC1CCC(F)(F)CC1
Product: CS(=O)(=O)O
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (S)-tert-butyl 1-(4,4-difluorocyclohexyl)-3-hydroxypropan-2-ylcarbamate (25.7 g, 0.088 mol) in dry CH2Cl2 (300 mL) was added Et3N (35.4 g, 46.2 mL) at 0 to −5° C. A solution of methanesulfonyl chloride (20.1 g, 0.1754 mol) in dry CH2Cl2 (150 mL) was added dropwise at the same temperature. After addition, the mixture was allowed to warm to rt gradually. 300 mL of water was added and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with 10% aq citric acid, satd aq NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give methanesulfonic acid (S)-2-(tert-butoxycarbonylamino)-3-(4,4-difluorocyclohexyl)propyl methanesulfonate (28.8 g, 89%), which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): 4.57 (d, J=6.8 Hz, 1H), 4.27 (m, 1H), 4.16 (m, 1H), 3.97 (m, 1H), 3.03 (s, 3H), 2.40-1.20 (m, 11H), 1.44 (s, 9H); MS (E/Z): 372 (M+H+).