Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-:22])([O-])=O.[Na+].[Na+].CCO[C:28]([CH3:30])=O>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:30]2[CH:28]=[CH:12][C:11]([NH:16][CH:19]=[O:22])=[CH:10][CH:9]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=CNc1ccc(-c2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
To 4-(benzyloxy)-1-chloro-2-nitrobenzene (394 mg, 1.5 mmol) N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)formamide (370 mg, 1.5 mmol) in 6 mL dioxane was added 3 mL of a 1 M Na2CO3 (aq) solution and Tetrakis(triphenylphosphine)palladium (52 mg, 0.045 mmol). The suspension was headed at reflux for 15 h under Ar atmosphere and cooled to rt. It was added EtOAc (80 mL) and washed with brine (50 mL), water (2×80 mL), and dried over MgSO4. After solvent removal, the residue was chromatographed (hexane/EtOAc) to afford N-(4′-(benzyloxy)-2′-nitrobiphenyl-4-yl)formamide as a yellow solid (395 mg, 75%). MS (ESI) m/z 349 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][Zn+]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:29][C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH3:32])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Cc1ccccc1C[Zn+]
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccccc3C)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=476 [M+Na]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:26][N:27]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[N:28]1.[Cl:36]CCl>>[Cl:36][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[S:32]([C:29]2[CH:30]=[CH:31][N:27]([CH3:26])[N:28]=2)(=[O:34])=[O:33])=[CH:3][CH:4]=1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: ClCCl
Reactant: O=C1NCCc2ccc(NCc3ccccc3)cc21
Solvent: c1ccncc1
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2ccc3c(c2)C(=O)NCC3)n1
Yield: 41 %

Procedure:
To a stirred solution of 7-benzylamino-3,4-dihydro-2H-isoquinolin-1-one (100 mg, 0.34 mmol) and pyridine (63 μl, 0.77 mmol) in anhydrous dichloromethane (2 ml) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (138 mg, 0.77 mmol) and the reaction heated at reflux for 15 hrs. The reaction was cooled and the solvent evaporated in vacuo. The crude residue was purified by flash column chromatography (50% ethyl acetate in dichloromethane) to afford the title compound as a colourless solid (63 mg, 41%). HPLC retention time 4.16 min. Mass spectrum (ES+) m/z 431 (M+H).
Reaction SMILES: C([SiH]([CH2:6][CH3:7])CC)C.[C:8]([C:13]1C=CC=[C:18]2[C:14]=1[CH2:15][C:16](=[O:22])[NH:17]2)(=O)[CH2:9][CH2:10][CH3:11].F[C:24](F)(F)C(O)=O>>[CH2:9]([C:8]1[CH:13]=[C:14]2[C:18](=[CH:6][CH:7]=1)[NH:17][C:16](=[O:22])[CH2:15]2)[CH2:10][CH2:11][CH3:24]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[SiH](CC)CC
Reactant: CCCC(=O)c1cccc2c1CC(=O)N2
Product: CCCCc1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
Triethylsilane (2.3 g) was added to 2 g 4-butanoyl-2-oxindole in 20 mL of trifluoroacetic acid at room temperature and the solution stirred for 3 hours. The reaction was poured into ice water to give a red oil which solidified after standing. The solid was collected by vacuum filtration, washed with water and hexane and dried to give 1.7 g (91% yield) of the title compound as an off-white solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].O>C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:22](=[O:24])[CH3:23])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To an ice-cold solution of 4-phenoxy-phenylamine (1.0 g, 5.39 mmol) in 10 ml of DCM was added triethylamine (0.90 ml, 5.93 mmol) followed by acetyl chloride (0.50 g, 6.47 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), water was added extracted with DCM (3×50 mL). The combined organics was dried (Na2SO4), filtered and concentrated to get the desired product (1.20 g, crude yield).
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH2:11][CH2:12][CH3:13].[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[N:6]([S:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:24])=[O:23])[CH:5]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[C:3]=1[CH2:11][CH2:12][CH3:13]
Reactant: CCCc1c(C(=O)OC)c[nH]c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCCc1c(C(=O)OC)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 85.2 %

Procedure:
Using methyl 5-bromo-4-propyl-1H-pyrrole-3-carboxylate (2.96 g), sodium hydride (60% in oil, 634 mg) and benzenesulfonyl chloride (2.33 g), a procedure as in Reference Example 41 was performed to give the title compound as colorless crystals (yield 3.96 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.[N:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]([NH:25][NH2:26])=O)=[CH:22][C:17]=2[NH:16][CH:15]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[S:36][C:23]([C:21]2[CH:20]=[CH:19][C:18]3[NH:14][CH:15]=[N:16][C:17]=3[CH:22]=2)=[N:25][N:26]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)s2)c(Cl)c1

Procedure:
The compound was synthesized starting from 3-(2,4-dichlorophenyl)propionic acid (220 mg; 1 mmol), benzimidazol-5-carbohydrazide (176 mg; 1 mmol), Lawesson's reagent (606 mg; 1.5 mmol) and POCl3 (0.137 ml; 1.5 mmol) as described in method 3; yield: 0.016 g (4.3%);
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([CH:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[CH2:11]([CH:14]1[CH2:19][CH2:18][CH:17]([CH:20]2[CH2:25][CH2:24][CH:23]([O:26][CH2:27][CH2:28][CH:29]=[O:30])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13]
Reactant: CCCC1CCC(C2CCC(OCCCO)CC2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(OCCC=O)CC2)CC1
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
DMSO in an amount of 2.13 ml (0.03 mol) was added dropwise to a mixture of 1.74 ml (0.02 mol) of oxalic acid chloride and 40 ml of dichloromethane at -50° C. and stirred for 10 min. While keeping inside of the reaction system at -60°C., this solution was added dropwise with a solution of 2.82 g (0.01 mol) of the 4-(4-propylcyclohexyl)-(3-hydroxypropyloxy)cyclohexane obtained in the second stage and dissolved in 20 ml of dichloromethane and stirred for 1 hour. To this solution was added 14 ml of triethylamine, temperature of the solution was returned to a room temperature, stirred for 15 min, and the solution was added with 80 ml of an aqueous solution saturated with ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate. After the magnesium sulfate was separated, the solvent was distilled off under a reduced pressure, and the residue was subjected to a silica gel column chromatography (eluate: toluene/ethylacetate (9/1)) to obtain 1.93 g of a crude 4-(4-propylcyclohexyl)-(3-oxopropyoxy) cyclohexane. This product was recrystallized from 12 ml of ethanol to obtain 1.3 g (yield 46%) of 4-(4-propylcyclohexyl)-(3-oxopropyloxy)cyclohexane.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29]Br.C(N(CC)CC)C>CC(C)=O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=C(CCCCBr)Nc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCN(CCCCC(=O)Nc1ccc2ccccc2c1)C1CCc2ncsc2C1

Procedure:
9 is prepared from 1C and 9A using the same method as for 6 with acetone as solvent and triethylamine as base. Reaction temperature is 50° C. After evaporation of the solvent the residue is suspended in water, alkalized with sodium hydroxide solution and extracted three times with dichloromethane. After evaporation of the combined organic phases the product is crystallized as salt of maleic acid from acetonitrile/diethylether.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:26](=[O:28])[CH3:27])[O:15][N:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:6]=1
Reactant: NCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC(c2ccc(-c3ccncc3)cc2)=NO1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a flame dried flask containing (R)-4,5-Dihydro[3-[4-(4-pyridinyl)phenyl]-5-(hydroxymethyl)]isoxazole (440 mg, 1.73 mmol) in methylene chloride (20 mL) at 0° C. under an inert atmosphere is added triethylamine (0.36 mL, 2.60 mmol) and methanesulfonyl chloride (0.14 mL, 1.82 mmol). The reaction is slowly warmed to ambient temperature, stirred 3 hours, and quenched with water (25 mL). The organic phase is separated, washed with saturated NaHCO3 (25 mL) and saline (25 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]-methyl]isoxazole (580 mg, 1.73 mmol) is dissolved in tetrahydrofuran (4 mL), isopropanol (4 mL), and concentrated ammonium hydroxide (4 mL) in a thick wall resealable vessel and heated to 100-110° C. for 15 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with saline (20 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole (320 mg, 1.57 mmol) is dissolved in methylene chloride (15 mL) and cooled to 0° C. under an inert atmosphere. Pyridine (0.31 mL, 3.78 mmol) and acetic anhydride (0.15 mL, 1.57 mmol) are added to the cooled solution and stirred 20 hours at ambient temperature. The reaction is concentrated in vacuo, diluted with methylene chloride (50 mL), washed with saline (25 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.14, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 244-245° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[N:9]([CH2:30][CH3:31])[CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41](OS(C(F)(F)F)(=O)=O)[CH:40]=1>>[CH3:35][O:36][C:37](=[O:57])[CH2:38][C:39]1[CH:40]=[C:41]([C:12]2[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:19])[F:20])=[CH:16][C:11]=2[CH2:10][N:9]([CH2:30][CH3:31])[C:8]([O:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:34][CH:33]=2)=[O:32])[CH:42]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:44]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccc(F)cc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid 4-fluoro-benzyl ester and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:16]([O:15][C:13]([N:12]1[C:11]2[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=2[NH:1][C:28]1=[O:30])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)[nH]c(=O)n2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.1 %

Procedure:
Part 2. To a chilled solution of methyl 3-amino-4-[(tert-butoxy)carbonylamino]benzoate (0.40 g, 1.5 mmol) in CH2Cl2 (10 mL) and triethylamine (0.21 mL, 1.5 mmol) was added a solution of triphosgene (161 mg, 0.54 mmol) in CH2Cl2 (6 mL) over 5 min. The reaction was stirred at room temperature for 2 hr, diluted with CH2Cl2, washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography using 50% ethyl acetate in CH2Cl2 as eluent to give methyl 1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.27 g, 61%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30]Cl)[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[C:15]([S:20][CH:21]([NH:28][C:29](=[O:32])[CH2:30][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CCl)c2ccncc2)cc1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2SC(NC(=O)CN2CCOCC2)c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(4-tert-Butylphenyl)-2-(2-chloroacetylaminopyridin-4-ylmethylthio)pyridine-3-carboxamide (Compound No. 16-1, 50 mg, 0.11 mmol) was suspended in morpholine (1.0 mL), and the mixture was stirred for 2 hours at 80° C. in the sealed tube. Ethyl acetate (50 mL) was added to the reaction mixture, the whole was washed with water (50 mL) and brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting solid was filtered off with diethyl ether and dried under reduced pressure to give 17 mg of the target compound as a pale yellow solid. (Yield 32%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:15]>CO>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH2:15])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Solvent: CO
Product: Nc1ncnc2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.6 g of 4-chloro-7-nitroquinazoline in 50 ml 7N ammonia in methanol was stirred overnight at rt and concentrated to dryness. The solid was suspended in water, filtered, rinsed with water followed by ether and dried overnight in vacuum oven to provide 0.98 g of 7-nitroquinazolin-4-amine (Compound 98-2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O.C>CS(C)=O.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([C:17]3([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30]
Reactant: COC1(c2ccc(C#Cc3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COC1(c2ccc(/C=C/c3cc(F)cc(F)c3NC(=O)C(C)(C)C)cc2)CCOCC1

Procedure:
The product from Example 6 (3.0 g) was dissolved in dimethylsulphoxide and Pd(dba)2 (200 mg) was added. The mixture was treated with H2 at atmospheric pressure until gas uptake ceased. On completion, the reaction was added to water (500 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extracts were washed with water (2×300 ml) and then dried on MgSO4, and filtered. Removal of the solvent in vacuo gave a yellow oil which was dissolved in diethyl ether, treated with charcoal, then filtered through. Hyflo. Removal of the solvent from the filtrate gave the crude title product. Precipitation from ethyl acetate/40-60° petroleum ether afforded the title product as a white solid; mp 150-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH:11]1[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCC2CC2)cc1
Temperature: 80 °C

Procedure:
5.0 g (28.9 mmol) 4-bromophenol, 3.93 g (43.4 mmol) (chloromethyl)cyclopropane and 7.99 g (57.8 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction mixture is diluted with water and extracted with DCM. The organic layer is dried with MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1[CH:30]=[CH:31]C2N(O)N=[N:35][C:33]=2[CH:34]=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59]NC1CCNCC1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59][CH:29]1[CH2:30][CH2:31][N:35]([C:16](=[O:18])[CH2:15][C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:19])[CH2:33][CH2:34]1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)nc1
Reactant: On1nnc2ccccc21
Reactant: Clc1ccccc1SNC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCC(Sc2ccccc2Cl)CC1)Nc1ccc(-c2ccccc2)nc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a stirred solution of N-(6-phenyl-pyridin-3-yl)-malonamic acid (0.07 g, 0.00024 mole) in DMF (1 mL) was added DIPEA (0.153 g, 0.00120 mole), HOBt (0.039 g, 0.00029 mole) and EDCI.HCl (0.055 g, 0.00029 mole). After 2 minutes (2-chloro-phenylsulfanyl)-piperidin-4-yl-amine hydrochloride (0.076 g, 0.00029 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.07 g (63%) of 3-[4-(2-chloro-phenylsulfanyl)-piperidin-1-yl]-3-oxo-N-(6-phenyl-pyridin-3-yl)-propionamide. LC-MS purity: 466.13 (M+1)+, 93.65%, 1H NMR (DMSO-d6): δ 10.5 (s, 1H), 8.8 (d, 1H), 8.2 (d, 1H), 8.1 (d, 2H), 8.0 (d, 1H), 7.6-7.2 (m, 6H), 4.3 (d, 1H), 3.9 (d, 1H), 3.6-3.5 (m, 3H), 3.0 (t, 1H), 2.0 (m, 2H), 1.7-1.6 (m, 1H), 1.5-1.4 (m, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:18][C:15]([F:16])([F:17])[C:13]1[CH:12]=[CH:11][C:7]2[C:8](=[O:10])[O:9][C:1](=[O:2])[NH:5][C:6]=2[CH:14]=1
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2c(=O)o1
Reaction time: 2 h

Procedure:
A solution of phosgene (9.9 g) in toluene (100 ml) was added dropwise to a stirred solution of 2-amino-4-trifluoromethylbenzoic acid (6.9 g) and sodium carbonate (3.2 g) in water (100 ml) cooled in ice. Coolant was removed, the mixture was stirred for 2 hours, and the resulting solid was collected by filtration. The solid was dissolved in ethyl acetate and the solution was dried over anhydrous magnesium sulphate and then evaporated under reduced pressure. The resulting solid was crystallised from ethyl acetate to give the novel compound 7-trifluoromethyl-1H-3,1-benzoxazine-2,4-dione, m.p. 243°-245° (dec.)
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[C:13](Cl)(=O)[C:14](Cl)=O.C[N:20]([CH3:23])C=O>ClCCl>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([NH:20][CH2:23][C:14]12[CH2:13][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(CBr)ccc1Cl
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-bromomethyl-2-chloro-benzoic acid (Example 71a, 12.4 g) in dichloromethane (250 ml) and dimethylformamide (0.12 ml) at 0° C. was added oxalyl chloride (8.7 ml). The cooling bath was removed and the solution allowed to warm to room temperature. Once gas evolution had ceased the solution was concentrated in vacuo. The residue was redissolved in dichloromethane (300 ml), cooled to 0° C. and treated with diisopropylethylamine (12.4 ml) and adamantylmethylamine (7.54 ml). After 15 min, at 0° C. the solution was poured into diethyl ether (1 L) and washed with 1 N aqueous hydrochloric acid followed by brine. The organics were dried over magnesium sulphate and concentrated in vacuo to give the title compound as a white powder (19 g)