Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][C:10]1[N:11]=[C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[CH3:26])(=[O:18])=[O:17])[S:13][CH:14]=1)(=O)=[O:5].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.Cl>C1COCC1.O>[OH2:5].[OH2:5].[Cl:25][C:21]1[C:20]([CH3:26])=[C:19]([S:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[N:11]=2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCn2ccnc2)cs1
Reaction time: 1.5 h

Procedure:
NaH (95% dry, 32 mg, 1.28 mmol) was added to a stirred solution of EXAMPLE 191A (250 mg, 0.61 mmol) and imidazole (46 mg, 0.67 mmol) in THF (10 mL) at room temperature. The mixture was stirred for 2 h at 40° C. when additional imidazole (41 mg, 0.61 mmol) and NaH (95% dry, 15 mg, 0.61 mmol) was added. The reaction was allowed to proceed for 1.5 h and was then neutralized by adding aqueous HCl (2 M). The solvent was evaporated and the resulting crude material was dissolved in TFA and purified by reversed phase flash chromatography on LiChroprep RP-18. The product was gradient eluting with (CH3CN in H2O/0.4% conc. HCl) to yield (80 mg, 0.21 mmol, 34%): MS (Ionspray, [M+H]+) m/z 382. Anal. Calcd. (found) for C15H15ClN4O2S2.2 H2O: C, 43.0 (42.9)%; H, 4.6 (4.3)%; N, 13.4 (13.7)%.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Cl:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 1.77 g N-chlorosuccinimide in 50 ml DMF (dimethylformamide) was added dropwise to a mixture of 3.0 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide at room temperature. The resulting solution was stirred overnight at room temperature and then poured into 800 ml water. The precipitate was collected, washed with water and dried (P2O5) under vacuum to give 3.1 g solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.O=[S:19](Cl)Cl>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[C:4]([CH:3]=1)=[N:10][S:19][N:9]=2
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1cc2nsnc2cc1Cl
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a solution of 4,5-dichlorobenzene-1,2-diamine (3.0 g, 0.017 mol) and triethylamine (9.45 mL, 0.068 mol) in dichloromethane (120 mL) was added SOCl2 (4.92 mL, 0.068 mol) dropwise at room temperature. The resulting reaction mixture was heated to reflux for 20 h. The reaction mixture was then allowed to cool to room temperature, and quenched with water carefully. The resulting mixture was extracted with dichloromethane, dried over Na2SO4 and concentrated on a rotary evaporator to give a dark solid as the crude compound. The crude compound was purified by flash column chromatography (silica gel, CHCl3) to afford 5,6-dichlorobenzo[1,2,5]thiadiazole as an off-white crystalline solid (2.35 g, 68% yield). 1H NMR (CDCl3 500 MHz): δ: 8.19 (t, 2H, J=8.5 Hz). 13C NMR (CDCl3, 500 MHz): δ 153.07, 135.28, 121.51. Anal. calcd. for (C6H2Cl2N2S): C, 35.14; H, 0.98; N, 13.66. Found: C, 35.08; H, 1.01; H, 13.56. m.p: 108-110° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:30](O)=[O:31])[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[S:35][C:36]([CH3:49])=[C:37]([CH3:48])[C:38]=1[C:39]([C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)=[O:40].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:30](=[O:31])[NH:33][C:34]4[S:35][C:36]([CH3:49])=[C:37]([CH3:48])[C:38]=4[C:39](=[O:40])[C:41]4[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=4)[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:22]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1sc(NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)CN(C(=O)OC(C)(C)C)C2)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (0.438 g, 0.999 mmol), and (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (0.241 g, 0.908 mmol) in DCM (20 mL) at 0° C. was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDC.HCl) (209 mg, 1.090 mmol). The reaction was warmed to rt and stirred overnight, before it was concentrated to dryness. The residue was purified by flash chromatography (hexane/EtOAc) to give tert-Butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-((3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)carbamoyl)-azetidine-1-carboxylate as an orange oil (382 mg). LRMS (M+Na)+: 708 m/z.
Reaction SMILES: Cl.[C:2](=[NH:13])([O:9][CH:10]([CH3:12])[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[S:22][N:23]([CH3:38])[C:24](=[O:37])[O:25][C:26]1[C:34]2[O:33][C:32]([CH3:36])([CH3:35])[CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:38][N:23]([C:24]([O:25][C:26]1[C:34]2[O:33][C:32]([CH3:36])([CH3:35])[CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)=[O:37])[S:22][N:13]=[C:2]([O:9][CH:10]([CH3:11])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(SCl)C(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CC(C)OC(=N)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=NSN(C)C(=O)Oc1cccc2c1OC(C)(C)C2)c1ccccc1

Procedure:
To a solution of isopropyl benzimidate hydrochloride (18.0 g, 90 mmoles) in methylene chloride (100 ml) at 0° under an atmosphere of dry nitrogen is added a solution of triethylamine (28 ml, 200 mmoles) in a small stream with stirring. To this mixture is added a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl N-chlorothio(methyl)carbamate (26 g, 90 mmoles) in methylene chloride (80 ml) in a dropwise fashion. The reaction mixture is stirred for two hours at 0° and then washed in turn with water, 2N hydrochloric acid and saturated sodium bicarbonate. The organic phase is dried over anhydrous magnesium sulfate and the solvent is removed under reduced pressure. The residue is poured onto a column of silica gel. Elution of the column with a solvent consisting of 15 parts ether and 85 parts Skellysolve B gives from the appropriate fraction isopropyl N-[[methyl[[[2,3-dihydro-2,2-dimethyl-7-benzofuranyl]oxy]carbonyl]amino]thio]benzimidate as a yellow oil.
Reaction SMILES: [C:1]([C:6]1([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH:19]1([C:6]2([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CCCC(=O)C1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)C1(C2CCCCC2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 119.5 %

Procedure:
2.5 g (7.4 mmol) of tert-butyl 4-butyryl-4-cyclohexylpiperidine-1-carboxylate (cf. preparation 17-1-4) are diluted in a mixture comprising 40 mL of dichloromethane and 8 mL of trifluoroacetic acid. The mixture is stirred at room temperature for 2 hours and the reaction is then stopped by adding aqueous 1N NaOH solution and the organic compounds are extracted with dichloromethane. The organic phase is dried and then concentrated. 2.1 g of 1-(4-cyclohexylpiperidin-4-yl)butan-1-one in the form of a colourless oil are obtained in a yield of 100%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:28])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N:7][C:6]=2[N:20]=1.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:1][C:2]1[C:3]([C:21]2[C:22]([CH3:28])=[CH:23][CH:24]=[CH:25][C:26]=2[CH3:27])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[N:7][C:6]=2[N:20]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCN(CC)CCCNc1ncc2cc(-c3c(C)cccc3C)c(N)nc2n1
Reactant: CC(C)(C)N=C=O
Product: CCN(CC)CCCNc1ncc2cc(-c3c(C)cccc3C)c(NC(=O)NC(C)(C)C)nc2n1

Procedure:
Prepared as described in Example 21, starting from 0.50 g of 7-amino-6-(2,6-dimethylphenyl)-2-(3-diethylamino-propylamino)-pyrido[2,3-d]pyrimidine from Example 114 and 0.17 mL of tert-butyl isocyanate. The product was purified by reverse phase preparative HPLC on a C18 reverse phase column, eluting with a solvent gradient starting from 95% of 0.1% trifluoroacetic acid in water/5% of 0.1% trifluoroacetic acid in acetonitrile to 65% of 0.1% trifluoroacetic acid in water/35% of 0.1% trifluoroacetic acid in acetonitrile, mp 86-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Cl:10])[CH:12]=2)=[O:9])[O:4][N:3]=1
Reactant: O=C(O)c1cc(Br)no1
Reactant: Nc1ccc(F)c(Cl)c1
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(Br)no1

Procedure:
This material was prepared according to the procedure of Example 1, Step C, using 3-bromoisoxazole-5-carboxylic acid and 3-chloro-4-fluoro aniline as starting materials. MF=C10H5BrClFN2O2; LCMS calculated for C10H5BrClFN2O2 (M+H)+: m/z=319.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:8])[CH2:6][NH2:7].C(O[C:12](=O)[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Cl:22])[CH:16]=1)C>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C:12]2[NH:7][CH2:6][CH2:5][N:8]=2)=[CH:16][C:17]=1[Cl:22]
Reactant: NCCN
Reactant: CCOC(=O)CNc1ccc(Br)c(Cl)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Clc1cc(NCC2=NCCN2)ccc1Br
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
To dry toluene (4 ml) under an inert atmosphere at 0° C. was added a toluene solution of trimethylaluminium (1.90 ml, 3.79 mmol, 2 M solution). A solution of ethylenediamine (0.25 ml, 3.79 mmol) in toluene (1.5 ml) was then added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 100 min at this temperature before being re-cooled to 0° C. To this mixture was added dropwise a solution of (4-bromo-3-chloro-phenylamino)-acetic acid ethyl ester (0.56 g, 1.90 mmol) in toluene (3 ml). The reaction mixture was then heated at 95° C. for 45 min and then cooled first to room temperature and finally to 0° C. The mixture was quenched by dropwise addition of methanol (1 ml) and when all gas evolution had ceased the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: dichloromethane/methanol=gradient 100:0-98:2) to yield a yellow gum; MS (ISP): 292.1, 290.0, 288.1 ([M+H]+.).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1ccc(Br)cc1
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
Product: O=Cc1ccc(-c2ccc(F)cc2)cc1
Yield: 69.4 %

Procedure:
A solution of 4-bromobenzaldehyde (1.0 g, 5.4 mmol, 1.0 eq) and 4-fluorophenylboronic acid (0.75 g, 5.4 mmol, 1.0 eq) in toluene was purged with nitrogen for 15 minutes and degassed under vacuum. Dry K2CO3 (1.12 g, 8.12 mmol, 1.5 eq) and tetrakis catalyst (0.3 g, 0.27 mmol, 0.05 eq) were added under nitrogen. The reaction mixture was refluxed under nitrogen for 12 h, quenched with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under vacuum. The residue was purified by silica gel (60-120) column chromatography using 5-10% ethyl acetate/hexane as the eluent to afford the desired compound (0.75 g, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.29-7.35 (t, 2H), 7.77-7.83 (t, 2H), 7.86-7.88 (d, 2H), 7.96-7.98 (d, 2H), 10.03 (s, 1H). MS (ESI): 201.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:27]3[N:28]=[CH:29][S:30][C:26]=3[C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncsc1-c1ccc(F)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncsc3-c3ccc(F)cc3)n2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.93 min; [M+H]+=411.03.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[O:18]=[C:19]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CCC>[O:18]=[C:19]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:23][CH2:22]1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CC(=O)N3CCCC3)CC2)ncn1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.50 g, 3.86 mmol) and diisopropylethylamine (0.499 g, 3.86 mmol) were suspended in n-butanol and then 1-(2-oxo-2-pyrrolidin-1-ylethyl)piperazine 17-1 (0.762 g, 3.86 mmol) was added. The reaction was stirred at 150° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and air dried. 1H-NMR (CD3OD): 7.96 ppm (s, 1H); 5.72 ppm (s, 1H); 3.55 ppm (m, 6H); 3.44 ppm (t, 2H); 3.24 ppm (s, 2H); 2.60 ppm (t, 2H); 1.98 ppm (m, 2H); 1.88 ppm (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH2:9].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH2:9])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=C(c1ccccc1O)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(c1ccccc1OC(c1ccccc1)(c1ccccc1)c1ccccc1)n1ccnc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a suspension of 1-[1-(2-hydroxyphenyl)vinyl]imidazole (500 mg) and triethylamine (407 mg) in dry methylene chloride (5 ml) is added trityl chloride (1.12 g) under stirring at room temperature, and the mixture is stirred at room temperature for 1 hour. To the mixture ice water is added and extracted with methylene chloride. The methylene chloride extract is dried on anhydrous sodium sulfate, and then concentrated. The residue is chromatographed on a column of silica gel, and eluted with methylene chloride-methanol (3-5%). The eluate is concentrated and the residue is crystallized from isopropyl ether and a small amount of petroleum ether to give 1-[1-(2-trityloxyphenyl)vinyl]imidazole (525 mg). mp. 149°-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:35])[CH2:33]Br)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:35])[CH2:33][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=2)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CBr)N[C@H]1CCN(Cc2ccccc2)C1
Reactant: COc1cc(O)ccc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCC(=O)N[C@H]2CCN(Cc3ccccc3)C2)ccc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
(S)-(+)-1-Benzyl-3-aminopyrrolidine (6 g, 34 mmol) was dissolved in dichloromethane (12 ml). To this solution, a solution of bromoacetyl chloride (5.46 g, 34 mmol) in dichloromethane (5 ml) was added at room temperature. The mixture was stirred at room temperature for 16 hours. The mixture was filtered, washed with dichloromethane and dried in vacuo to afford 7.3 g (64%) of (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride as a solid which was used directly in the next step. 4-Hydroxy-2-methoxybenzaldehyde (2.39 g, 16 mmol) was dissolved in DMF (10 ml) and potassium carbonate (7.3 g, 52 mmol) was added followed by a suspension of the above (3S)-N-(1-benzylpyrrolidin-3-yl)-2-bromoacetamide hydrochloride (3.5 g, 10 mmol) in DMF (20 ml). The resulting mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between water (100 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were washed with saturated sodium chloride (3×15 ml), dried (MgSO4) and concentrated in vacuo. The residue (4 g) was crystallised from a mixture of diethyl ether and heptane, filtered and dried in vacuo to afford 2.7 g (71%) (S)-N-(1-benzylpyrrolidin-3-yl)-2-(4-formyl-3-methoxyphenoxy)-acetamide as a solid. M.p.: 96-100° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[O:10]=[C:9]1[C:5]2=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:2](=[O:1])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH2:7][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Reactant: ClCc1ccccc1
Solvent: CN(C)C=O
Product: O=C1C2=C(c3ccccc3)N(Cc3ccccc3)C(=O)C2=C(c2ccccc2)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
5.6 parts of potassium t-butylate are added to a suspension of 5.8 parts of 1,4-diketo-3,6-diphenylpyrrolo-[3,4-c]-pyrrole in 70 parts of dimethylformamide at 20° C. and the mixture is stirred at 20° C. for 1 hour. 7.6 parts of benzyl chloride are then added to the mixture and the mixture is kept at 65° C. for 2 hours. After cooling to 20° C., the reaction product is filtered off and washed with a little dimethylformamide and then with acetone and hot water. After drying, 4.5 parts of 1,4-diketo-2,5-dibenzyl-3,6-diphenylpyrrolo-[3,4-c]-pyrrole (formula XVII) are obtained and, if necessary, can be crystallised from dimethylformamide. Yellow-orange crystals of melting point 290°-292° C. are formed. ##STR21##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH2:27])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1.[CH3:28][CH:29]([O:31][C:32]1[C:33](=O)[C:34](=[O:40])[C:35]=1[O:36]C(C)C)[CH3:30]>C(O)C>[CH3:1][O:2][C:3]1[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:33]5[C:34](=[O:40])[C:35](=[O:36])[C:32]=5[O:31][CH:29]([CH3:30])[CH3:28])[CH:25]=4)[NH:20][CH:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:6]=[N:7][CH:8]=1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(N)cc23)CC1
Solvent: CCO
Product: COc1cncnc1N1CCN(CCCc2c[nH]c3ccc(Nc4c(OC(C)C)c(=O)c4=O)cc23)CC1
Temperature: 80 °C
Yield: 67.2 %

Procedure:
A solution of 3-[3-[4-(5-methoxy-4-pyrimidyl)-1-piperazinyl]propyl]-5-aminoindole (6) (0.208 g, 0.56 mmol) and 3,4-bis (1-methylethoxy) cyclobut-3-ene-1,2-dione4 (2) (0.112 g, 0.56 mmol) in 5 mL of absolute ethanol was stirred at room temperature for 66 h and then it was heated at ca. 80° C. (oil-bath temperature) for 4 h. The cooled mixture was filtered and the residue was washed with ethanol and then dried in vacuo to give the title compound (0.190 g, 64%) as a slightly pinkish solid, mp 140°-143° C.: IR (KBr) 3312, 1800, 1720, 1607, 1588 cm-1 ; 1H NMR (DMSO-d6, 200 MHz) δ 10.80 (s, 1H), 10.7 (br s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.48 (m, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.14 (s, 1H), 7.06 (m, 1H), 5.40 (m, 1H), 3.81 (s, 3H), 3.65 (br s, 4H), 3.42 (q, J=7.0 Hz, 0.6H, CH3CH2OH), 2.67 (m, 2H), 2.43 (m, 4H), 2.35 (m, 2H), 1.82 (m, 2H), 1.41 (d, J=6.1 Hz, 6H), 1.04 (t, J=7.0 Hz, 0.9H, CH3CH2OH). Anal. Calcd for C27H32N6O4. 0.5 H2O. 0.3 C2H6O: C, 62.85; H, 6.65; N, 15.94. Found: C, 62.85; H, 6.46; N, 16.17.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.Cl.[OH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:14]([OH:13])[CH2:15]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@H]1CCCN(c2nnc3ccc(F)cn23)C1
Temperature: 175 °C
Yield: 37.5 %

Procedure:
A mixture of Intermediate 24b (394 mg, 2.30 mmol), (S)-3-hydroxypiperidine hydrochloride (1.00 g, 7.27 mmol) and DIPEA (1.27 mL, 7.30 mmol) in DMA (8 mL) was heated in the microwave at 170-180° C. for 9.5 h. The cooled mixture was concentrated in vacuo and applied to an SCX-2 cartridge (70 g), washing with methanol then eluting basic components with 0.4-2 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the title compound as a pale brown solid (204 mg, 38%). LCMS (Method 3): Rt 2.02 min, m/z 237 [MH+].
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21]OS(C)(=O)=O)[CH2:10]1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[C:1]([CH2:21][C@@H:11]1[CH2:10][C@@H:9]([CH2:8][C:7]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:5]([Cl:4])[CH:6]=2)[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(Cl)c(Cl)c2)C[C@H]1CC#N
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 98.3 %

Procedure:
Sodium cyanide (4.3 g, 87.4 mmol) was added to a solution of crude (2S,4R)-4-(3,4-dichlorobenzyl)-1-tert-butoxycarbonyl-2-(methanesulfonyloxymethyl)pyrrolidine (7.7 g, 17.5 mmol) in dry DMSO (120 mL) and the mixture was heated at 80° C. with stirring for 3.5 hrs. The reaction mixture was cooled and worked up between EtOAc and aqueous Na2CO3. Vacuum drying of the product afforded 6.34 g (17.2 mmol) of (2S,4R)-2-(cyanomethyl)-4-(3,4-dichloro-benzyl)-1-tert-butoxycarbonylpyrrolidine as an amber oil.