Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:21](O)[CH3:22]>>[CH2:21]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10])[CH3:22]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCC(Cc1ccccc1)(C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of diethyl benzylmalonate (20.0 g, 80 mmol) in ethanol (500 mL) was added potassium hydroxide (4.7 g, 84 mmol) as pellets. The mixture was stirred at room temperature for 24 h, and concentrated to dryness in vacuo. The residue was dissolved in water (300 mL), transferred to a separatory funnel, and washed with ether (2×150 mL). The aqueous solution was acidified to pH˜2 by adding conc. HCl, and extracted with ether (2×400 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness in vacuo, yielding the title compound as an oil residue (16.9 g, 95%) which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1[C:13]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[C:28]([CH3:29])=[CH:27][C:26]([C:30](O)=[O:31])=[N:25]1)=[O:14].[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:33]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:30]([C:26]1[CH:27]=[C:28]([CH3:29])[N:24]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:13]([N:4]2[C@H:3]([CH2:2][OH:1])[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5]2)=[O:14])[N:25]=1)=[O:31])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCNCCCC
Reactant: Cc1cc(C(=O)O)nn1-c1ccc([N+](=O)[O-])cc1C(=O)N1Cc2ccccc2C[C@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2ccc([N+](=O)[O-])cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (5)-1-(2-(3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-nitrophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid (14.0 g, 32.1 mmol) in DMF (150 mL) were added dibutylamine (8.6 mL, 48.2 mmol), EDC.HCl (9.2 g, 48.2 mmol), HOBT (5.63 g, 41.7 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (300 mL×2) twice. The combined organic layers were washed with water (300 mL), brine (100 mL), dried over sodium sulphate and concentrated invacuo. The residue was purified on silica gel (100-200 mesh) to afford the title compound as and ‘off white’ solid 9 g (51%). Rf=0.47 (25% EtOAc in hexane); 1H NMR (400 MHz, DMSO-d6): δ 8.62-8.22 (m, 2H), 8.00-7.80 (m, 1H), 7.30-6.84 (m, 4H), 6.60-6.35 (m, 1H), 5.20-3.80 (m, 3H), 3.79-2.40 (m, 9H), 2.38-2.20 (m, 3H), 1.60-0.50 (m, 14H); LC-MS: m/z 548.0 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]=O)[C:17]=3[CH:23]=2)[C:3]1=[O:24].[CH2:25]([NH:29][CH2:30][CH2:31][SH:32])[CH2:26][CH2:27][CH3:28].C(O)C>O1CCCC1>[CH2:25]([N:29]1[CH2:30][CH2:31][S:32][CH:21]1[C:18]1[C:17]2[CH:23]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]3=[O:24])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)[CH2:26][CH2:27][CH3:28]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C=O)c3c2)c1=O
Reactant: CCCCNCCS
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN1CCSC1c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxaldehyde (0.500 g, 1.41 mmol), 2-(butylamino)ethanethiol (0.250 ml, 1.69 mmol), ethanol and tetrahydrofuran is stirred overnight at room temperature and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate-hexanes to afford the title compound as a light yellow solid (0.210 g, 31.7%, mp 78-82° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[NH4+].[C:14]([NH:17][CH2:18][C:19]1[O:23][C:22]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)=[CH:21][CH:20]=1)(=[O:16])[CH3:15]>CC(C)=O>[C:14]([NH:17][CH2:18][C:19]1[O:23][C:22]([C:24]2[N:25]=[C:26]([NH:29][C:11]([NH:12][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[S:10])[S:27][CH:28]=2)=[CH:21][CH:20]=1)(=[O:16])[CH3:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Reactant: CC(=O)NCc1ccc(-c2csc(N)n2)o1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CC(=O)NCc1ccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)o1

Procedure:
Benzoyl chloride (2.67 ml) was dropped to a refluxing solution of ammonium thiocyanate (1.92 g) in acetone (50 ml) and the mixture was refluxed for 15 minutes. 4-(5-Acetylaminomethylfuran-2-yl)-2-aminothiazole (5.20 g) was added portionwise to the refluxing mixture. After the mixture was refluxed for further two hours, the solvent was evaporated in vacuo and the residue was mixed with water and ethyl acetate. The resulting precipitate was collected by filtration and washed with ethyl acetate to afford 4-(5-acetylaminomethylfuran-2-yl)-2-(3-benzoylthioureido)thiazole (5.50 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10](O)[CH3:11])([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.CS([Cl:26])(=O)=O>CN(C)C=O>[Cl:26][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:11]
Reactant: CC(O)c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Cl)c1ccccc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
311 g 1-(2-nitrophenyl)ethanol (XI-1) (95.8% purity, 1.78 mol) are dissolved in 3000 ml dimethyl formamide in a 6 liter three-necked flask equipped with a stirrer, dropping funnel and thermometer. 921.4 g (7.13 mol) diisopropylethylamine are added in a single portion, stirred for 5 minutes, then 612.5 g (5.35 mol) methanesulfonyl chloride are added dropwise between 20 to 35° C. with good cooling. After the reaction has subsided, it is stirred for another 90 hours at room temperature, and the solvent is removed under vacuum. Then the residue dissolved in ethyl acetate, washed 3 times with water, dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified by column chromatography (silica gel, 9:1 hexane/acetone). 219 g of 1-(1-chloroethyl)-2-nitrobenzene (100% purity by HPLC, 66.2% theoretical yield) are obtained as a brown oil [logP (pH 2.3)=2.87].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:14])[C:6](=[CH:10][C:11]=1[O:12][CH3:13])[C:7](O)=[O:8].[CH:15]([NH2:17])=O>O>[CH3:13][O:12][C:11]1[CH:10]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[N:14]=[CH:15][NH:17][C:7]2=[O:8]
Reactant: NC=O
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 190 °C
Reaction time: 3 h
Yield: 18 %

Procedure:
A mixture of 4,5-dimethoxyanthranilic acid (19.7 g, 100 mmol) and formamide (10 ml) was heated at 190° C. for 5 hours. The mixture was allowed to cool to approximately 80° C. and water (50 ml) was added. The mixture was then allowed to stand at ambient temperature for 3 hours. Collection of the solid by suction filtration, followed by washing with water (2×50 ml) and drying in vacuo, yielded 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g, 18% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:13]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Reaction time: 24 h

Procedure:
To the commercially available 6-bromo-naphthalene-2-ol (1) (1 equi.) and benzyl bromide (2) (1 equi.) in DMF (3mL/mmole), cesium carbonate (1.25 equi.) was added at room temperature. The reaction mixture was stirred at that temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane (1:1), washed with brine, over MgSO4, and concentrated in vacuo.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=3)=[CH:22][CH:21]=2)[CH:4]=[C:5]2[C:10]=1[N:9]1[C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:12]3[N:13]=[C:8]1[N:7]([CH3:17])[C:6]2=[O:18].ClC(Cl)(Cl)C(O)=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:17][N:7]1[C:6](=[O:18])[C:5]2=[CH:4][N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=4)=[CH:22][CH:21]=3)[C:2]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:10]2[N:9]2[C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:12]3[N:13]=[C:8]12
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c2N2C1=N[C@@H]1CCC[C@@H]12
Reactant: Nc1ccccc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Nc3ccccc3)c2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 100 °C
Yield: 14.5 %

Procedure:
Crude (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-1-chloro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (approx. 0.03 mmol) is dissolved in anhydrous CH2Cl2, and then trichloroacetic acid (5.2 mg, 0.03 mmol) is added, followed by aniline (5.8 uL, 0.06 mmol). The reaction mixture is heated in a Biotage microwave instrument at 100° C. for 2 hours. The mixture is purified by a semi-preparative HPLC to give 2.2 mg of product as solids. MS (ESI) m/z 507.2 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[Cl:3][CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:7][N:6]=1.[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[ClH:3].[ClH:1].[ClH:3].[CH3:13][N:12]([CH2:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:4][S:17][C:16](=[NH:15])[NH2:18])[CH:10]=1)[CH3:14]
Reactant: NC(N)=S
Reactant: CN(C)Cc1ccnc(CCl)c1
Agent: Cl
Solvent: CCO
Product: CN(C)Cc1ccnc(CSC(=N)N)c1
Yield: 125 %

Procedure:
2-Chloromethyl-4-(dimethylaminomethyl)pyridine dihydrochloride (14.67 g) was added to a refluxing solution of thiourea (4.34 g) in ethanol (120 ml) and the solution refluxed for 3 hours, whereupon solid precipitated. After cooling the mixture (ice bath), the solid was filtered and recrystallised from methanolethanol to give S-(4-dimethylaminomethyl-2-pyridylmethyl)isothiourea trihydrochloride (11.88 g), m.p. 175°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[Cl:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:13]([Cl:12])([F:22])[F:23])=[CH:16][CH:17]=1)=[O:7]
Reactant: O=C(O)c1ccc(F)c(Br)c1
Reactant: Nc1ccc(OC(F)(F)Cl)cc1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 1.2 using 3-bromo-4-fluorobenzoic acid and 4-(chlorodifluoromethoxy)aniline to afford an off-white solid. UPLC-MS (Condition 3) tR=1.25 min, m/z=394.0 [M+H]+, m/z=391.9 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.37 (d, J=9.17 Hz, 2H) 7.57 (t, J=8.68 Hz, 1H) 7.84-7.91 (m, 2H) 8.03 (ddd, J=8.62, 4.83, 2.32 Hz, 1H) 8.32 (dd, J=6.60, 2.20 Hz, 1H) 10.52 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1.C([O-])([O-])=O.[K+].[K+].C1CCN2C(=NCCC2)CC1>CO>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: BrCC1CCCO1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CC1(C)C(=O)N(CC2CCCO2)c2cc([N+](=O)[O-])c(N)cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 2-bromomethyl-tetrahydro-furan (1.7 ml; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 30° C. for 3 days. After aqueous work-up the crude material is de-acetylated in MeOH (150 ml) using DBU (2,3 ml) at reflux. After aqueous work-up and purification by RP chromatography 5-amino-3,3-dimethyl-6-nitro-1-(tetrahydro-furan-2-ylmethyl)-1,3-dihydro-indol-2-one (1.88 g) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:18]2[C:19]([CH3:27])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)[S:12][C:13]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:18]2[C:19]([CH3:27])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=23)[S:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nn2ccccc2c1-c1nc(-c2ccc(F)cc2F)c(C(=O)O)s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a suspension of methyl 4-(2,4-difluorophenyl)-2-(2-methylpyrazolo[1,5-a]pyridin-3-yl)-1,3-thiazole-5-carboxylate (250 mg, 0.649 mmol) obtained above in THF (5 mL) and MeOH (5 mL), was added 2N aqueous solution of sodium hydroxide (1 mL) and the mixture was stirred for 2 h at 60° C. To the mixture, was added a 2:1 mixture of EtOAc and THF (60 mL) and 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with a 2:1 mixture of EtOAc and THF (10 mL). The combined organic layers were washed with brine (5 mL) and then dried over anhydrous sodium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain title compound (225 mg, 93%) as a pale yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:25])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]O)=[CH:17][C:16]=1[O:23][CH3:24].CCCCCCC>ClCCl>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:25])[NH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][Cl:3])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1NC(=O)Nc1ccccc1C
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1cc(CCl)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
7.65 ml (104.8 mmol) of thionyl chloride were added dropwise with ice cooling to a suspension of 15 g (52.4 mmol) of 4-(3-(2-methylphenyl)ureido)-3-methoxybenzyl alcohol in 300 ml of dichloromethane. The reaction mixture was subsequently stirred at room temperature for 3 hours, allowed to stand overnight and then poured onto 1000 ml of n-heptane. The heptane was decanted off from the deposited oil, the residue was again suspended with n-heptane and the heptane was decanted off. This process was repeated a further two times. The residue was then dissolved in dichloromethane and poured into 800 ml of ice-cold diisopropyl ether. It was subsequently stirred with ice cooling for 2 hours, and the product was filtered off with suction and washed with diisopropyl ether. After drying over phosphorus pentoxide, 12 g (75%) of the title compound were obtained.
Reaction SMILES: Cl.Cl.[C:3]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:26])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>C(Cl)Cl>[C:3]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:26])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(CN1CCC(N)CC1)c1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CN1CCC(NC(=O)C2CC2)CC1)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
A stirred solution of 1-[2-(4-benzoylphenyl)propyl]-4-aminopiperidine dihydrochloride, 150 ml. of methylene dichloride and 10.5 g. (0.105 mole) of triethylamine was treated in portions with a solution of 3.9 g. (0.039 mole) of cyclopropanecarbonyl chloride in methylene dichloride. When addition was complete the mixture was allowed to stand at ambinet temperature for twenty-five hours and then washed two times with water, once with aqueous potassium carbonate and once with brine and then dried and taken to dryness in vacuo. Recrystallization of the residue from diethyl ether gave 1-[2-(4-benzoylphenyl)propyl]-4-cyclopropanecarbonylaminopiperidine, m.p. 159°-160° C.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]12[N:37]([C:38](=[O:40])[CH3:39])[CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[C:38]([N:37]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][N:32]([C:20]([C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25]([N:26]([CH3:27])[CH3:28])=[O:29])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=1)=[O:22])[CH2:33]2)(=[O:40])[CH3:39]
Reactant: CC(=O)N1C2CCC1CNC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CC(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Yield: 62 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 1-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanone following amide formation method 3 which gave 2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (43 mg, 62% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.80 (s, 1H) 8.53 (d, J=8.59 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 7.86 (dd, J=8.59, 2.02 Hz, 1H) 6.65 (s, 1H) 4.80-4.73 (m, 1H) 4.73-4.25 (m, 3H) 3.86-3.41 (m, 2H) 3.16 (s, 7H) 2.64-2.42 (m, 2H) 2.23-1.99 (m, 8H) 1.91 (br. s., 2H) 1.83-1.61 (m, 3H); HR-MS (m/z MH+) 531.28 RT 4.27 min
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[C:19]([Cl:21])=[O:20]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:18](=[O:22])[C:19]([Cl:21])=[O:20])=[CH:8]2)=[CH:16][CH:17]=1
Reactant: Clc1ccc(Cn2ccc3ccccc32)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: O=C(Cl)C(=O)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-chlorobenzyl)-1H-indole (2.0 g) in dry ethyl ether (5 ml) kept under stirring and cooled to 0° C. is added drop by drop with a solution of oxalyl chloride (0.85 ml) in dry ethyl ether (2 ml). Afterwards the reaction is left at room temperature for 2 h. The separated solid is recovered by filtration, washed with dry ethyl ether and dried under vacuum at 40° C. to give 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (1.64 g).
Reaction SMILES: [OH:1][C:2]([CH3:13])([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21].CCOCC.O>CN(C)C=O>[CH3:13][C:2]([O:1][Si:20]([CH3:22])([CH3:21])[CH3:19])([CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[CH:4]
Reactant: C#CC(C)(O)COc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(C)(COc1ccccc1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The hydroxyl group of this alkyne is protected by dissolving 2 parts of the butyne in 5 parts by volume of dimethylformamide and successively treating the reaction mixture with 2 parts of imidazole and 1.2 parts of trimethylsilylchloride. The reaction mixture is stirred at room temperature for 1 hour and poured into ether/water. The ethereal layer is washed with water and dried over anhydrous sodium sulfate. Isolation by low pressure liquid chromatography on silica gel provides 3-methyl-3-trimethylsilyloxy-4-phenoxy-1-butyne.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[N:8]=1.IC>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([CH3:2])[CH:10]=[C:9]([Cl:13])[N:8]=1
Reactant: Clc1cccc(Cl)n1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
A solution of n-BuLi (21.1 mL, 33.8 mmol, 1.6 M) in THF was cooled to −78° C. before a solution of 2,6-dichloropyridine (5.0 g, 33.8 mmol) in THF (36 mL) is added dropwise over a period of 20 min. The reaction mixture is stirred at −78° C. for 30 min, and then iodomethane (4.79 g, 33.8 mmol) is added. The mixture is stirred for 30 min before it is quenched with sat. aq. NH4Cl solution at −78° C. The mixture is extracted with diethyl ether, the org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 19:1 to give 2,6-dichloro-4-methyl-pyridine (2.34 g) as a colourless oil containing the regio isomer 2,6-dichloro-3-methyl-pyridine; LC-MS: tR=0.89 min, [M+1]+=161.97.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([Br:43])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[C:42]2[C:37](=[CH:38][C:39]([Br:43])=[CH:40][CH:41]=2)[CH2:36][CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: NC1CCc2cc(Br)ccc21
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3cc(Br)ccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-5-bromo-indane
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[O:13])[N:7]([CH2:8][C:9]([CH3:10])([CH3:11])[CH3:12])[C:2]=1[NH2:1]
Reactant: CC(C)(C)Cn1c(N)c(N=O)c(=O)[nH]c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O

Procedure:
To a suspension of 6.0 g of XXVII in 100 ml of water was added 13.0 g of sodiumdithionite in portions. The green crystals were filtered off and washed with water. Yield 4.0 g (XXVIII).