Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[S:13][C:12]([CH3:14])=[CH:11][C:9]=2[N:10]=1.C(N(CC)CC)C>C(O)C>[Cl:4][C:5]1[N:6]=[C:7]([N:2]([CH3:3])[CH3:1])[C:8]2[S:13][C:12]([CH3:14])=[CH:11][C:9]=2[N:10]=1
Reactant: CNC
Reactant: Cc1cc2nc(Cl)nc(Cl)c2s1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc2nc(Cl)nc(N(C)C)c2s1
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 50% aqueous dimethyl amine (0.15 g) in ethanol (5 mL) were added 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (0.25 g) and triethylamine (0.12 g) at room temperature, and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with chloroform and water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with 1 M hydrochloric acid and saturated brine and then dried with anhydrous magnesium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure and crystallized with diethyl ether to obtain 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.16 g). (2) To a mixture of 2-chloro-N,N,6-trimethylthieno[3,2-d]pyrimidin-4-amine (0.150 g), Pd2(dba)3 (0.033 g), (±)-BINAP (0.067 g), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.26 g), and 1,4-dioxane (8 mL) was added sodium t-butoxide (0.21 g) under nitrogen atmosphere, and the mixture was stirred at 60° C. for 5 h. The reaction mixture was diluted with ethyl acetate and water, then the interlayer was removed by Celite filtration, and the organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform/methanol, and NH silica gel, ethyl acetate) to obtain light yellow amorphous 1-((3R,4R)-3-(4-dimethylamino-6-methylthieno[3,2-d]pyrimidin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.097 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:26]1[CH2:30][CH2:29][C@@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@@H:28]([O:31]/[N:32]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])[CH2:27]1
Reactant: NO[C@@H]1CCNC1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Product: C/C(=N\O[C@@H]1CCNC1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 60 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) (25 mg, 0.082 mmol) and (R)—O-(pyrrolidin-3-yl)hydroxylamine dihydrochloride in 60% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.92 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.41 (dd, 1H), 6.10 (s, 2H), 5.30 (s, 1H), 5.09 (s, 1H), 3.31 (m, 3H), 2.38 (s, 3H), 2.25 (m, 2H). LCMS (method B): [MH]+=389, tR=1.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)=[CH:4][CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:33])[CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc(Cl)cc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.8 %

Procedure:
Combine 10-((S)-3-[2-(4-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (430.9 mg, 0.99 mmol), formaldehyde (88.0 μL, 1.08 mmol, 37% in water), and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (313.5 mg, 1.48 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion, extract the aqueous with dichloromethane and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/methanol (95:5) to give 365.2 mg (82%) of the title compound as a brown foam: mp 79°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][NH:14][C:15](=[O:36])[CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[CH3:35])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[Cl:34][C:30]1[C:29]([CH3:35])=[C:28]([N:17]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH2:16][C:15]([NH:14][CH2:13][C:12]2[CH:37]=[CH:38][C:9]([OH:8])=[CH:10][CH:11]=2)=[O:36])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(OCc3ccccc3)cc2)c2cccc(Cl)c2C)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(O)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 66.8 %

Procedure:
668 mg of N-[4-(benzyloxy)benzyl]-N2-(3-chloro-2-methylphenyl)-N2-[(4-methylphenyl)sulfonyl]glycinamide was dissolved in 5.00 mL of methanol and 2.00 mL of THF, and 70 mg of 10% Pd—C (Kawaken, AD type, water content 54%) was added thereto, followed by stirring at room temperature for 6.5 hours under a hydrogen atmosphere. The reaction liquid was filtered through Celite, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50 to 30:70) to obtain a product, which was recrystallized from ethanol/water to obtain 373 mg of N2-(3-chloro-2-methylphenyl)-N-(4-hydroxybenzyl)-N2-[(4-methylphenyl)sulfonyl] glycinamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:33][C:34](=O)[CH2:35][C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:44]2[O:48][N:47]=[C:46]([CH3:49])[CH:45]=2)[CH:39]=1)=[O:37])(C)(C)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:13]([NH:14][C:34](=[O:33])[CH2:35][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([C:44]3[O:48][N:47]=[C:46]([CH3:49])[CH:45]=3)[CH:39]=2)=[O:37])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:10]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [5-amino-2′-fluoro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example J5) (200 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K4) (160 mg, 0.53 mmol) according to the general procedure M. Obtained as a white solid (40 mg).
Reaction SMILES: C(O[C:4](=[O:27])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:9]=1)=[O:6])C.[O:28]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[Li+]>C1(C)C(C)=CC=CC=1>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:41][CH:40]=2)=[O:27])=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)OCC)cc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)Nc2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 3 h
Yield: 85.6 %

Procedure:
A solution of N-(4-dodecyloxyphenyl)oxalamic acid ethyl ester (10 g, 0.026 mol), 4-phenoxyaniline (5 g, 0.026 mol) and lithium t-butoxide (0.2 g, 0.0026 mol) in xylene (50 mL) isheated to gentle reflux. A distillate of ethanol/xylene is slowly collected; the reaction volume is kept at 50 mL by adding xylene. Heating and distillation continued for 3 hours. The reaction mixture is cooled, the solids are collected and washed sequentially with warm ethyl acetate, ethanol, water and finally ethanol. There is obtained 11.5 g white solid mp: 179–181.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:39][O:38][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:35](O)=[O:36])[N:21]([C@H:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:26][CH2:27][CH3:28])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:46][C:47](=[O:65])[C@@H:48]([NH2:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[C:62]([C:59]1[CH:58]=[CH:57][C:56]([C:53]2[CH:54]=[CH:55][C:50]([CH2:49][C@H:48]([NH:64][C:35]([C@@H:20]3[CH2:19][C:18]4[CH:17]=[C:16]5[O:38][CH2:39][C@H:13]([C:10]6[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]7[CH:40]=[CH:41][C:42]([Cl:43])=[C:2]([Cl:1])[CH:3]=7)=[CH:12][CH:11]=6)[O:14][C:15]5=[CH:24][C:23]=4[CH2:22][N:21]3[C@H:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[O:36])[C:47]([OH:46])=[O:65])=[CH:51][CH:52]=2)=[CH:61][CH:60]=1)#[N:63]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CCC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-butyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 868.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[C:18]([CH3:47])=[C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH:39][C@@H:40]([CH:44]([CH3:46])[CH3:45])[C:41]([OH:43])=[O:42])(=[O:38])=[O:37])=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)=[O:22])[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[C:17]2[C:18]([CH3:47])=[C:19]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([S:36]([NH:39][C@@H:40]([CH:44]([CH3:45])[CH3:46])[C:41]([OH:43])=[O:42])(=[O:38])=[O:37])=[CH:32][CH:31]=4)=[CH:28][CH:29]=3)=[O:22])[O:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]
Reactant: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(OCCNC(=O)OC(C)(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(-c3ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc3)cc2)oc2cccc(OCCN)c12

Procedure:
The product of Example 177, (S)-2-(4′-{[4-(2-tert-butoxycarbonylamino-ethoxy)-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid, was treated with 40% TFA/methylene chloride solution at ambient temperature for four hours to afford (S)-2-(4′-{[4-(2-amino-ethoxy)-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid as a brown solid (TFA salt). MS: calc'd for {M−H]−: 564.65. Found: 564.51.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:14]([N:17]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[C:18](=[O:29])[C:19]1[CH:24]=[CH:23][C:22](Br)=[C:21]([O:26][CH2:27][CH3:28])[CH:20]=1)([CH3:16])[CH3:15].Cl>N1C(C)=CC(C)=CC=1C>[CH:30]1([N:17]([CH:14]([CH3:15])[CH3:16])[C:18](=[O:29])[C:19]2[CH:24]=[CH:23][C:22]([O:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:21]([O:26][CH2:27][CH3:28])[CH:20]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CCOc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Br
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CCOc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Oc1cc(OC)c(OC)c(OC)c1
Reaction time: 18 h

Procedure:
A slurry of cuprous oxide (300 mg, 2.1 mmol) in a solution of 3,4,5-trimethoxyphenol (736 mg, 4.0 mmol) and 4-bromo-3-ethoxybenzoic acid N-isopropyl-N-cyclohexyl amide (1.47 g, 4.0 mmol) in 2,4,6-collidine (20 ml) is refluxed with stirring under a nitrogen atmosphere for 18 hr. The reaction is cooled, poured onto dilute aqueous HCl and extracted three times with ethyl acetate. The combined organic layers are washed twice with saturated aqueous NaCl solution, twice with 5% NaOH solution, twice with saturated NaCl solution and dried (Na2SO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. This material is chromatographed on silica gel using mixtures of ethyl acetate and hexane as the eluents to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:11][N:12](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:8][C:5]1[N:6]=[CH:7][C:2]([C:11]#[N:12])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(Cl)ncc1C#N
Temperature: 95 °C
Reaction time: 12 h

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyridine (5.0 g, 22.48 mmol) in DMF (80 mL) was purged with nitrogen for 15 minutes. At this point, Zn(CN)2 (3.96 g, 33.7 mmol) and Pd(Ph3P)4 (2.60 g, 2.25 mmol) were added, successively. The resulting suspension was stirred at 95° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature, and filtered to remove inorganic solid. The solvent (DMF) was evaporated to provide the crude residue as an oil, which was purified on silica gel and eluted with 0-30% ethyl acetate/hexanes to afford the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(Cl)Cl>[C:2]1([NH:1][C:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
Aniline (2.03 g, 25.0 mmol) was dissolved in CH2Cl2 (30 mL). To the solution were added pyridine (2.22 mL, 27.5 mmol) and decanoyl chloride (5.25 g, 27.5 mmol) in an ice bath. After stirring for 3 h at room temperature, the reaction mixture was poured into 1M HCl (30 mL) and the mixture extracted with CH2Cl2 (3×100 mL). The organic extracts were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated to give 5.62 g (22.8 mmol, 91%) of N-phenyldecanamide as a white solid, mp 65-66° C. (lit5 mp 65-66° C.); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H, J=6.9 Hz), 1.26 (m, 12H), 1.72 (m, 2H), 2.35 (t, 2H, J=7.8 Hz), 7.10 (t, 2H, J=7.8 Hz), 7.31 (t, 1H, J=7.8 Hz) 7.50 (t, 2H, J=7.9 Hz); 13C NMR (75 MHz, CDCl3) δ 13.9, 22.5, 25.7, 29.2, 29.2, 29.3, 29.3, 31.7, 37.5, 120.1, 124.0, 128.7, 138.1, 172.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:25]=[CH:24][C:10]2[S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Cl)=[CH:14][C:13]=3[C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+]>O1CCCC1>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:25]=[CH:24][C:10]3[S:11][C:12]4[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCCCl)c1ccc2sc3ccc(C(=O)CCCCl)cc3c2c1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCN1CCCCC1)c1ccc2sc3ccc(C(=O)CCCN4CCCCC4)cc3c2c1
Temperature: 125 °C
Reaction time: 24 h

Procedure:
A mixture of 28.0 g (0.072 mole) of 2,8-bis(4-chlorobutyryl)dibenzothiophene, 49.4 g (0.58 mole) of piperidine and 2.0 g of potassium iodide in 200 ml of tetrahydrofuran is heated at 125°C with stirring for 24 hours in a Parr general purpose bomb. The reaction mixture is cooled, filtered, and the filtrate is evaporated in vacuo leaving a residue which is washed with water and recrystallized twice from acetone to give 2,8-bis(4-piperidinobutyryl)dibenzothiophene, M.P. 93°-95°C.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C=CC([CH:15]2N[C:18]([C:20]3C=CC(OC)=[CH:22][C:21]=3OCC)=[N:17][CH:16]2[CH:31]2CCCC2)=CC=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[N:47]([C:48]([N:50]3[CH2:55]CN(C)C[CH2:51]3)=[O:49])[C:46]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=3[O:65][CH2:66][CH3:67])=[N:45][CH:44]2[CH2:68][CH:69]2[CH2:73][CH2:72][CH2:71]C2)=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:38]=[CH:39][C:40]([CH:43]2[N:47]([C:48]([N:50]3[CH2:55][CH2:31][CH:16]([N:17]4[CH2:22][CH2:21][CH2:20][CH2:18]4)[CH2:15][CH2:51]3)=[O:49])[C:46]([C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=3[O:65][CH2:66][CH3:67])=[N:45][CH:44]2[CH:68]2[CH2:69][CH2:73][CH2:72][CH2:71]2)=[CH:41][CH:42]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-4-cyclopentyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole, trifluoroacetate salt (Example 19) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 579.3104, calculated for C33H44N4O3Cl [(M+H)+]579.3097.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]2[C:6]3[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]=3[CH:14]=[CH:15][CH:16]=2)C.[H-].[Na+].[CH2:19](I)[CH2:20][CH2:21][CH3:22]>>[CH2:19]([N:9]1[C:10]2[C:6]3[C:5](=[CH:16][CH:15]=[CH:14][C:7]=3[C:8]1=[O:13])[C:4]([S:3][CH3:1])=[CH:12][CH:11]=2)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCI
Reactant: CCSc1ccc2c3c(cccc13)C(=O)N2
Agent: [H-]
Agent: [Na+]
Product: CCCCN1C(=O)c2cccc3c(SC)ccc1c23

Procedure:
A mixture of 2.15 g of 6-(methylthio)-benz[cd]indol-2(1H)-one (Example 12), 0.6 g of 60% sodium hydride and 1.7 ml of butyl iodide in 70 ml are reacted as described in Example 16 giving 1.85 g of the desired product as a solid, m.p. 75°-77° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:6]1[C:5]2=[O:19].[C:20]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])([O:22][CH3:23])=[O:21]>>[C:20]([C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([N:12]1[C:7]2=[N:8][C:9]3[C:4]([C:5](=[O:19])[N:6]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=3)=[O:27])([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: O=c1c2cc(Br)ccc2nc2[nH]c3ccccc3n12
Product: COC(=O)c1ccccc1C(=O)n1c2ccccc2n2c(=O)c3cc(Br)ccc3nc12

Procedure:
6-(2-Carbomethoxybenzoyl)-2-bromobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 2-bromobenzimidazo[2,1-b]quinazolin-12(6H)one and 2-carbomethoxybenzoylchloride.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[CH3:16])=[CH:12]/[C:13]([OH:15])=O)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8](/[C:11](/[CH3:16])=[CH:12]/[C:13]([N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:15])=[CH:9][CH:10]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: C/C(=C\C(=O)O)c1ccc(CC(C)C)cc1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Product: C/C(=C\C(=O)N1CCC[C@H]1CN1CCCCC1)c1ccc(CC(C)C)cc1

Procedure:
130 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(Isobutyl)phenyl)but-2-enoic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[F:11].[Cl:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([F:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[F:11]
Reactant: COc1cc(F)c(Br)c(F)c1
Reactant: COC(=O)Cc1ccc(B(O)O)c(Cl)c1
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: [Na+]
Solvent: COCCOC
Product: COc1cc(F)c(-c2ccc(CC(=O)O)cc2Cl)c(F)c1
Temperature: 85 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
A solution of 4-bromo-3,5-difluoroanisole (645 mg, 2.89 mmol) and 2-chloro-4-(2-methoxy-2-oxoethyl)phenylboronic acid (Intermediate 2-6; 859 mg, 3.76 mmol) and sodium carbonate (2.89 mL, 5.78 mmol), tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.18 mmol) in DME (20 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was allowed to cool, evaporated and partitioned between EtOAc (75 mL), water (40 mL) and saturated brine (15 mL), The aqueous phase was acidified with 2M HCl and extracted into EtOAc (2×125 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 2-(2-chloro-2′,6′-difluoro-4′-methoxybiphenyl-4-yl)acetic acid (654 mg, 72.4%) as a white solid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@H:7]2[CH2:12][O:11][C@@H:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:9][CH2:8]2)=[CH:4][CH:3]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:22]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C@H:7]3[CH2:8][O:9][C@@H:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:11][CH2:12]3)=[CH:20][CH:21]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(O)cc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NCCC[C@H]1OC[C@@H](Oc2ccc(OC3CCCC3)cc2)CO1
Reaction time: 8 h

Procedure:
cis-N-{3-[5-(4-Hydroxyphenoxy)-[1,3]dioxan-2-yl]propyl}acetamide (18.6 mg, 0.063 mmol), cyclopentyl bromide (11.3 mg, 0.076 mmol) and cesium carbonate (24.6 mg, 0.076 mmol) were stirred in 3 ml of DMF at room temperature for 3 h. Addition of 11 mg of cyclopentyl bromide and 20 mg of cesium carbonate on each of two occasions was followed by stirring for a total of 8 h and concentrating, and the residue was taken up in ethyl acetate and water. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 8.5 mg (37%), M+H+: 364.22.