Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH2:6][CH2:5]2
Reactant: Clc1cc2cc[nH]c2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1cc2c(cc1Cl)NCC2
Yield: 90 %

Procedure:
5,6-Dichloroindole (D38) was reduced in the usual way with sodium cyanoborohydride in glacial acetic acid to give the title compound (D39) (1.18 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:33])[CH2:13][N:14]([C:16]([C@@H:18]2[CH2:22][C@@H:21]([S:23]CC3C=CC(OC)=CC=3)[CH2:20][NH:19]2)=[O:17])[CH3:15])=[CH:7][CH:6]=1)[CH3:2].[C:35]1([CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4](=[O:34])[C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[CH2:13][N:14]([C:16]([C@@H:18]2[CH2:22][C@@H:21]([SH:23])[CH2:20][N:19]2[S:44]([CH2:43][CH2:42][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:46])=[O:45])=[O:17])[CH3:15])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)CN(C)C(=O)[C@@H]2C[C@@H](SCc3ccc(OC)cc3)CN2)cc1
Reactant: O=S(=O)(Cl)CCCc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)CN(C)C(=O)[C@@H]2C[C@@H](S)CN2S(=O)(=O)CCCc2ccccc2)cc1

Procedure:
Analogously, (2S,4R)-4-(2-[[4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetylamino)-benzoic acid ethyl ester was treated with 3-Phenyl-propane-1-sulfonyl chloride folowed by deprotection according to 8.1. to give (2S,4R)-4-[2-[[4-Mercapto-1-(3-phenyl-propane-1-sulfonyl)-pyrrolidine-2-carbonyl]-methyl-amino]-acetylamino]-benzoic acid ethyl ester as colorless foam MS: 548 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[N:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl.Cl[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[C:20](=[O:24])[N:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:26])([F:28])[F:27]
Reactant: ClCc1ccncc1
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Agent: Cl
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1Cc1ccncc1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2(1H)-pyrimidinone and 4-(chloromethyl)pyridine hydrochloride. LC-MS (ESI): m/z 502 [M+H]+; 4.27 min (ret time).
Reaction SMILES: C(O[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][C:13]=1F)CCCCCCCCC.S(=O)(=O)(O)O>N1C=CC=CC=1.CO>[CH:12]1[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:19]#[C:18][C:15]2[CH:14]=[CH:13][CH:12]=[CH:17][CH:16]=2)=[CH:16][CH:17]=1
Reactant: C#Cc1ccc(OCCCCCCCCCC)c(F)c1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CO
Product: C(C#Cc1ccccc1)#Cc1ccccc1
Temperature: 25 °C
Yield: 225.9 %

Procedure:
To a 50 ml round bottom flask equipped with a magnetic stirrer and reflux condenser was added 300 mg 4-decyloxy-3-fluorophenylacetylene and 43 mg cupric acetate in 40 ml 1:1 pyridine/MeOH. The reaction mixture was refluxed for 2 hrs, allowed to cool to room temperature and then added dropwise into a stirred 9 M aqueous sulfuric acid solution at ice bath temperature. The resulting cream-like suspension was extracted with ethyl ether and sequentially washed with water (3x) and brine and dried with anhydrous magnesium sulfate yielding 289 mg of a yellow-brown solid. Flash chromatography (1% ethyl acetate/hexane) and recrystallization of the residue from 95% ethanol afforded 248 mg diphenyldiacetylene (V), 4,4'-didecyloxy-3,3'-difluoro diphenyldiacetylene, as pale yellow needles.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH:34]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH:34]1([NH:39][C:2]2[N:7]3[N:8]=[C:9]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccco3)nn12
Solvent: CCOC(C)=O
Product: c1coc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (200 mg, 0.53 mmol) was dissolved in 5 mL of cyclopentylamine. The solution was heated at 100° C. overnight, then cooled to room temperature. Ethyl acetate was added to dilute the reaction mixture, the organic phase was washed with water and brine and dried over magnesium sulfate. Filtration and concentration followed by purification with flash chromatography (1:4 ethyl acetate:hexanes) gave N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(2-furyl)pyrazolo[1,5-a]pyridin-7-amine (206 mg, 91%) as a yellow solid. 1H NMR (CDCl3): δ 8.20 (d, 1H), 7.68 (d, 1H), 7.62 (d, 1H), 7.32 (t, 1H), 6.92 (d, 1H), 6.59 (m, 2H), 6.05 (m, 2H), 5.11 (d, 1H), 4.43 (m, 1H), 4.04 (m, 1H), 2.14 (m, 4H), 1.87–1.56 (m, 12H). MS m/z 429 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH2:8][C:7]1([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]1)[C:6]2=[N:20]S(C(C)(C)C)=O>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:6]2=[NH:20])=[CH:10][C:11]=1[CH3:12]
Reactant: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1cc(C)c(Br)cc1C2=N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl-solution (4 M in 1,4-dioxane, 4.76 mL, 19.0 mmol) was added to a solution of N-(5′-bromo-4-methoxy-6′-methylspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 9, 812 mg, 1.90 mmol) in anhydrous 1,4-dioxane (8 mL). The resulting mixture was stirred under a nitrogen atmosphere at r.t. for 1 h. The mixture was concentrated and the residue was dissolved in a small amount of DCM (˜4-6 mL). Et2O (14 mL) was added and the solid was filtered off and washed with Et2O. The solid was partitioned between DCM (10 mL) and saturated aqueous NaHCO3 (8 mL). The phases were separated and the organic layer concentrated. The product (446 mg) was used directly in the next step: MS (EI) m/z 321, 323 [M+.].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:18](=[O:20])[CH3:19])=[CH:5][S:6][C:7]=1[C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12]C[C:10]=2[CH:9]=1.C1C2C(=CC(C3SC=C(C#N)C=3OC)=CC=2)CC1>>[CH2:14]1[C:15]2[C:16](=[CH:17][C:8]([C:7]3[S:6][CH:5]=[C:4]([C:18](=[O:20])[CH3:19])[C:3]=3[O:2][CH3:1])=[CH:9][CH:10]=2)[CH2:12][CH2:13]1
Reactant: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCCC2
Agent: COc1c(C#N)csc1-c1ccc2c(c1)CCC2
Product: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCC2
Yield: 75.8 %

Procedure:
Synthesis was carried out in the same manner as in Synthesis Method 2 (5) in Reference Synthetic Example 3 by using 4.5 g (0.0176 mol) of 5-(2,3-dihydro-1H-inden-5-yl)-4-methoxythiophene-3-carbonitrile to obtain 3.64 g of the desired product (yield: 75.8%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH:10]2[CH:14](I)[CH2:13][O:12][O:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:17](=O)([O-])[O-].[K+].[K+]>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>[CH3:1][O:2][C:3](=[O:16])[C:4]1[C:9]([CH:10]2[CH:14]([CH3:17])[CH2:13][O:12][O:11]2)=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccccc1C1OOCC1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1C1OOCC1C
Temperature: 105 °C
Reaction time: 10 h

Procedure:
A suspension of 5-iodo-2,3-dioxolanebenzoic acid methyl ester (0.1 g, 0.32 mmol), potassium carbonate (0.048 g, 0.35 mmol), tetrakis(triphenylphosphine)palladium (1 mol %) and trimethylboraxine (0.089 ml, 0.64 mmol) in 1,4-dioxane (5 ml) is stirred under nitrogen at 105° C. for 10 hours. Solvent is removed and the residue is taken in ethyl acetate (50 ml). This mixture is washed with water (30 ml), dried with sodium sulphate and evaporated. Purification by chromatography (ethyl acetate/hexane 5:95) gives 5-methyl-2,3-dioxolanebenzoic acid methyl ester; GC/MS: 194 (M+1)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.[NH:36]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]2)=[N:37]1.CN(C)[C@@H]1CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[N:33]1[CH:34]=[CH:35][C:30]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([N:36]4[CH:40]=[CH:39][C:38]([CH:41]5[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]5)=[N:37]4)[CH:3]=3)[N:7]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:6]=2)=[CH:31][CH:32]=1
Reactant: Ic1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc[nH]n2)C1
Agent: [Cu]I
Agent: CN(C)[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC(c2ccn(-c3ccc4c(c3)c(-c3ccncc3)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1
Temperature: 100 °C
Yield: 110.7 %

Procedure:
The mixture of 5-iodo-3-(pyridin-4-yl)-1-trityl-1H-indazole (281 mg, 0.5 mmol), tert-butyl 3-(1H-pyrazol-3-yl)piperidine-1-carboxylate (151 mg, 0.6 mmol), copper (I) iodide (19 mg, 0.1 mmol), rac-trans-N,N-dimethylcyclohexane-1,2-diamine (57 mg, 0.4 mmol), K2CO3 (552 mg, 4 mmol) in toluene (3 mL) was heated at 100° C. for 4 days. After cooling to room temperature, the reaction mixture was filtered through a pad of celite, and washed with EtOAc. The filtrate was concentrated and column purified with mixture of methanol, dichloromethane and ammonia to give tert-butyl 3-(1-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)-1H-pyrazol-3-yl)piperidine-1-carboxylate (380 mg).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C:14](=[O:26])[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:12][CH:11]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:11]1[CH:12]=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14](=[O:26])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[C:10]=1[CH3:9]
Reactant: CCOC(=O)c1ccc(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 82.8 %

Procedure:
N-Iodosuccinimide (6.89 g, 30.6 mmol) was added to a solution of ethyl 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylate (9.9 g, 30.5 mmol) in DCM (45 ml) and TFA (38 ml) under a nitrogen atmosphere. After 19 h stirring at ambient temperature the solvent was concentrated in vacuo. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue to neutralize the remaining TFA. The organic phase was collected, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with DCM/methanol (10:0.2) to give the title compound as a yellow solid (11.4 g, 83%).
Reaction SMILES: CC1C=CN=C(N[C:9](=[O:25])[C:10]2[CH:15]=[CH:14][C:13]([B:16]3[O:20][C:19]([CH3:22])([CH3:21])[C:18]([CH3:24])([CH3:23])[O:17]3)=[CH:12][CH:11]=2)C=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH2:34])[CH:29]=1>>[CH3:21][C:19]1([CH3:22])[C:18]([CH3:23])([CH3:24])[O:17][B:16]([C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:34][C:30]3[CH:29]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:33]=[CH:32][N:31]=3)=[O:25])=[CH:11][CH:12]=2)[O:20]1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Yield: 89 %

Procedure:
This compound was prepared, in an analogous manner as described in Intermediate 6, starting from 4-(trifluoromethyl)pyridin-2-amine, to afford the title compound (657.2 mg, 89%).
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.C(O)(=O)C.[C:14]([C:16]1[CH:22]=[C:21]([F:23])[C:19](N)=[C:18]([F:24])[CH:17]=1)#[N:15].[BrH:25]>[Cu]Br.O>[Br:25][C:19]1[C:21]([F:23])=[CH:22][C:16]([C:14]#[N:15])=[CH:17][C:18]=1[F:24]
Reactant: Br
Reactant: N#Cc1cc(F)c(N)c(F)c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(Br)c(F)c1
Reaction time: 1 h

Procedure:
24 g of sodium nitrite was added to 180 ml of concentrated sulfuric acid cooled to a temperature of at least 10° C. 38 ml of acetic acid was added to the mixture. 53 g of 4-cyano-2,6difluoroaniline was added gradually to keep the temperature of the solution between about 20°and 25° C. The mixture was stirred at 20°-25° C. for one hour. A solution was prepared by dissolving 60 g of copper (I) bromide in 180 ml of an aqueous 48% solution of hydrobromic acid. The mixture was added drop-wise to the solution and the solution was stirred at room temperature for 15 hours. Water was added to the solution, and the solution was extracted with chloroform and washed with water. The chloroform in the aqueous layer was distilled off and the residue was recrystallized from a solution mixture of methanol and acetone, to yield 25 g of 2-bromo-5-cyano-1,3-difluorobenzene.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8]Cl)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[N:4]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C=O)C>[C:27]1(=[O:37])[N:31]([CH2:2][C:3]2[CH:7]=[C:6]([CH2:8][N:31]3[C:30](=[O:32])[C:29]4=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]4[C:27]3=[O:37])[N:5]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[N:4]=2)[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1nc(CCl)cc1CCl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1nc(CN2C(=O)c3ccccc3C2=O)cc1CN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 12.8 g. (32.8 mmol) of the end product of Example 24, 18.5 g. (100 mmol) of potassium phthalimide, and 250 ml. of DMF was stirred and heated at 65° for 18 hours. After cooling, the mixture was poured over ice, washed with dil. brine, dried (MgSO4) and concentrated in vacuo. The residue was filtered through silica gel using EtOAc as an eluent. Removal of the solvent left the end product as a pale yellow solid, mp. 220°-224°. The analytical sample was prepared by recrystallization from acetone-hexane: pale yellow needles, mp 225°-226.5°.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(N2CCCCC2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(N2CCCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(piperidin-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 409.11 g/mol.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]1([C:14]2[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:7]1[C:2]([NH:19][C:16]2[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[NH:18][N:17]=2)=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Clc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of 2,3,5,6-tetrachloropyridine (0.20 g, 0.9 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (0.20 g, 1.8 mmol), and triethylamine (0.10 g, 1.4 mmol) in NMP (2 ml) was heated in a microwave at 200° C. for 30 min. The reaction was cooled to 25° C., quenched with water (10 ml), and extracted with MTBE (4×30 ml). The combined organic fractions were then dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=50:1) to give the title compound (0.035 g, 12%). MS: Calcd.: 303. Found: [M+H]+ 303.
Reaction SMILES: [N:1]1[O:2][C:3]2[CH2:4][CH2:5][CH2:6][CH:7]3[C:16]=2[C:15]=1[C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:8]3.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:8]2[CH:7]3[C:16]4=[C:3]([O:2][N:1]=[C:15]4[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=4)[CH2:4][CH2:5][CH2:6]3)=[CH:20][CH:19]=1
Reactant: c1ccc2c(c1)NC1CCCc3onc-2c31
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(CN2c3ccccc3-c3noc4c3C2CCC4)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In 40 ml dry DMF were combined 3.00 g 4,5,5a,6-tetrahydro-3H-isoxazolo[5,4,3-kl]acridine, 8.8 ml 4-fluorobenzylbromide and 3 g milled K2CO3. The mixture was stirred mechanically under nitrogen at ambient temperature for 2 days during which the reaction was complete. The reaction mixture was poured into excess water and extracted with DCM. The DCM layer was concentrated to a residue and the residue was triturated with 1:1 methanol/water and recrystallized from 1:1 DCM/hexanes to yield after drying 2.21 g needles, m.p. 214° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58].C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCCOc1ccccc1OB([O-])[O-]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOCCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 2-(propoxyethoxy)phenyl borate (155 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 12 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[2-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 114) (230 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-chlorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@@H:25]([CH3:28])[CH2:26][OH:27])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].[CH2:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](F)=[CH:35][CH:34]=1)[CH3:30].C(OCC)(=O)C>CC(N(C)C)=O>[OH:27][CH2:26][C@H:25]([CH3:28])[O:24][C:22]1[CH:23]=[C:8]([CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])[CH:21]=1)[O:7][C:36]1[CH:37]=[CH:38][C:33]([C:32]([O:31][CH2:29][CH3:30])=[O:40])=[CH:34][CH:35]=1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO)c2)cn1
Reactant: CCOC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3cnc(C)cn3)c2)cc1
Temperature: 130 °C
Yield: 3.1 %

Procedure:
Caesium carbonate (8.45 g, 26 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide (4 g, 13 mmol) and ethyl-4-fluorobenzoate (2.33 g, 13 mmol) in dimethylacetamide (70 mL) and the stirred mixture heated at 130° C. for 72 hours. The mixture was allowed to reach RT and ethyl acetate (100 mL) added. The mixture was washed with water (5×40 mL), brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50% ethyl acetate in isohexane, to give the desired compound (0.18 g)