Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[C:11](O)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].O>CS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:9][CH3:10])[O:8][CH:13]([CH3:14])[CH2:12][C:11]2=[O:15]
Reactant: COc1cc(O)ccc1Cl
Reactant: C/C=C/C(=O)O
Agent: CS(=O)(=O)O
Solvent: O
Product: COc1cc2c(cc1Cl)C(=O)CC(C)O2
Temperature: 23 °C

Procedure:
A solution of 1.0 g (6.3 mmol) 4-chloro-3-methoxyphenol and 5.4 g (6.3 mmol) crotonic acid in 15 ml methane sulfonic acid was heated at 95° C. under nitrogen for 20 hours. The reaction was cooled to 23° C., poured onto 150 ml ice and water and extracted with 100 ml ethyl acetate. The ethyl acetate extract was successively washed with 100 ml water, 2×100 ml 1N sodium hydroxide and 100 ml brine, dried over magnesium sulfate and concentrated in vacuo to a purple crystalline solid. This was purified by flash chromatography on 150 cc silica gel using chloroform as eluant to give the product as a yellow crystalline solid, 1.1 g (78%); m.p. 96°-100° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([O:17]C)[CH:8]=2)[N:6]=1.B(Br)(Br)[Br:20]>C(Cl)Cl>[BrH:20].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([OH:17])[C:10]([OH:16])=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=2)[N:6]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(-c2csc(N)n2)cc([N+](=O)[O-])c1O
Solvent: ClCCl
Product: Br
Product: Nc1nc(-c2cc(O)c(O)c([N+](=O)[O-])c2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 267.3 mg of 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol in 10 ml of dry methylene chloride is treated at -20° with 1.25 g of boron tribromide. After the addition the mixture is stirred at -20° for a further 1 hour and at room temperature without cooling for 18 hours. The reaction mixture is then evaporated, the residue is treated cautiously with water and stirred at 50° for 30 minutes. After cooling to room temperature the mixture is suction filtered and the crude product is removed by filtration and washed with a small amount of water. There is obtained 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide of m.p. 244°-246° (from methanol).
Reaction SMILES: COC(=O)NC(C(N1C(C2NC([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[NH:40][C:41](C7C8CC(CC8)N7C(=O)C(NC(OC)=O)C(C)C)=[N:42][CH:43]=6)=[CH:35][CH:34]=5)[CH:29]=4)[CH:24]=3)=CN=2)CC2(CC2)C1)=O)C(C)C.[CH3:63][O:64][C:65](=[O:104])[NH:66][CH:67]([C:71]([N:73]1[CH:78]([C:79]2[NH:80][C:81](C3C=CC4C(=CC=C(B5OC(C)(C)C(C)(C)O5)C=4)C=3)=[CH:82][N:83]=2)[CH:77]2[CH2:103][CH:74]1[CH2:75][CH2:76]2)=[O:72])[CH:68]([CH3:70])[CH3:69].[C:105]([O:109][C:110]([N:112]1[CH2:118][CH2:117][C:114]2([CH2:116][CH2:115]2)[CH2:113]1)=[O:111])([CH3:108])([CH3:107])[CH3:106].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:105]([O:109][C:110]([N:112]1[CH:118]([C:41]2[NH:40][C:39]([C:36]3[CH:35]=[CH:34][C:33]([C:28]4[CH:27]=[CH:26][C:25]5[C:30](=[CH:31][CH:32]=[C:23]([C:81]6[NH:80][C:79]([CH:78]7[CH:77]8[CH2:103][CH:74]([CH2:75][CH2:76]8)[N:73]7[C:71](=[O:72])[CH:67]([NH:66][C:65]([O:64][CH3:63])=[O:104])[CH:68]([CH3:69])[CH3:70])=[N:83][CH:82]=6)[CH:24]=5)[CH:29]=4)=[CH:38][CH:37]=3)=[CH:43][N:42]=2)[CH2:117][C:114]2([CH2:116][CH2:115]2)[CH2:113]1)=[O:111])([CH3:108])([CH3:106])[CH3:107]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Yield: 60 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl]-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example EZ) using [2-Methyl-1-(3-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (2.25 mmol), 645-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (2.39 mmol), and potassium carbonate (2M, 4.3 mL, 8.55 mmol). The reaction was performed under an argon atmosphere. The crude reaction was diluted in ethyl acetate, washed with water and purified by normal phase silica chromatography (50-100% Hexanes:EthylAcetate+10% Methanol). 6-{5-[4-(6-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (1.05 g, 60%) was obtained as a tan solid.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[S:25][CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30].[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:47][CH:48]=[CH:49][N:50]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:41]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:50][CH:49]=[CH:48][N:47]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54][C:24]2[S:25][CH:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[N:41]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: O=[N+]([O-])c1ccsc1NCCNc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(3-nitro(2-thienyl))amino]ethyl}aamine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-3-nitrothiophene in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[CH2:9]([N:4]1[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cc[nH]n1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccn(Cc2ccccc2)n1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 3-methyl-1H-pyrazole (5.00 g, 60.9 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (60%) (4.88 g, 203 mmol) in portions at 0° C. and stirred for 30 min under nitrogen. To the above mixture was added benzyl bromide (8.7 mL, 73.1 mmol). The reaction mixture was stirred for 1 h at room temperature, then carefully quenched with 150 mL of water. The aqueous phase was extracted with 3×30 mL of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 5.66 g (54%) of the title compound as light yellow oil.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[N:17]1[N:18]=[C:19]([SH:26])[N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12.CCN(C(C)C)C(C)C>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[N:17]1[N:18]=[C:19]([S:26][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)[N:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=12
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Sc1nnc2ccccn12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2nc(Sc3nnc4ccccn34)ccc2n1)C1CC1
Temperature: 120 °C
Yield: 187.2 %

Procedure:
N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (0.5 g, 1.52 mmol), [1,2,4]triazolo[4,3-a]pyridine-3-thiol (0.23 g, 1.52 mmol), Tris(dibenzylideneacetone)dipalladium(0) (84 mg, 0.09 mmol), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (106 mg g, 0.18 mmol), and DIEA (0.531 mL, 3.05 mmol) were dissolved in DME (15.2 mL) and heated in a microwave at 120° C. for 30 min. The reaction mixture was concentrated to dryness, reconstituted in DMSO, and purified by preparative LCMS to give N-(6-([1,2,4]triazolo[4,3-a]pyridin-3-ylthio)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (1 g, 43%) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ=11.17 (s, 1 H), 8.57-8.44 (m, 1 H), 8.03-7.94 (m, 1 H), 7.96-7.88 (m, 2 H), 7.59 (ddd, J=1.0, 6.6, 9.3 Hz, 1 H), 7.22-7.11 (m, 1 H), 7.11-7.03 (m, 1 H), 1.97-1.84 (m, 1 H), 0.83-0.73 (m, 4 H) ESI-MS:m/z 352.3 (M+H)+. MP 193-195° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O.O>CN(C)C=O>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCCC1CCCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(Tetrahydro-2H-pyran-3-yl)ethyl methanesulfonate (142 mg) was added and the stirring mixture heated at 60° C. for 3 h. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a brown solid, yield 138 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1.[OH:24]/[N:25]=[C:26](\Cl)/[C:27]1[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:29][N:28]=1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:23])[O:6][CH:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]4([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[O:24][N:25]=[C:26]([C:27]5[C:31]([C:32]([F:35])([F:33])[F:34])=[C:30]([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[O:29][N:28]=5)[CH:12]4[CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:4][O:3]1
Reactant: O/N=C(\Cl)c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: CC1(C)OCC(c2ccc3c(n2)CCC=C3N2CCOCC2)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OCC(c2ccc3c(n2)CCC2C(c4noc(-c5ccccc5)c4C(F)(F)F)=NOC32N2CCOCC2)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-7,8-dihydroquinolin-5-yl)morpholine (Preparation 15F, 0.194 g, 0.613 mmol) in dichloromethane (2 mL) was added a solution of (Z)—N-hydroxy-5-phenyl-4-(trifluoromethyl)isoxazole-3-carbimidoyl chloride (Intermediate 13, 0.210 g, 0.613 mmol) in dichloromethane (1 mL). The reaction mixture was cooled to 0° C., and triethylamine (0.093 mL, 0.674 mmol) was added dropwise over 2 min. The ice-bath was removed, and the resulting cloudy solution was stirred at room temperature for 30 min. The reaction mixture was diluted with dichloromethane (30 mL), washed with water (15 mL), dried over anhydrous sodium sulfate, and concentrated to give the morpholino-intermediate, 7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9b-morpholino-3-(5-phenyl-4-(trifluoromethyl)-isoxazol-3-yl)-3a,4,5,9b-tetrahydroisoxazolo[5,4-f]quinoline, as an orange oil. To the oil was added dichloroethane (3 mL) and TFA (0.071 mL, 0.920 mmol), and the reaction mixture was heated at 80° C. for 60 min. The reaction mixture was stirred overnight at room temperature. Additional TFA (0.071 mL, 0.920 mmol) was added, and the reaction mixture was heated at 80° C. for 6 h. The reaction mixture was diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of sodium bicarbonate (15 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by trituration with methanol with sonication afforded 44 mg of a 3:7 mixture of 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinolin-7-yl)ethane-1,2-diol and 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydroisoxazolo[5,4-f]quinoline as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]([CH3:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:21]O.C(Cl)(Cl)Cl.O1CCCC1.CS(Cl)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>C(N(CC)CC)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[N:9]([CH3:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[CH2:21][N:41]1[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]1
Reactant: CN1CCNCC1
Reactant: Cc1c(CO)nc2n1-c1ccccc1N(C)c1ccccc1-2
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCN(C)CC2)nc2n1-c1ccccc1N(C)c1ccccc1-2
Temperature: -20 °C

Procedure:
A sampmle of 3,9-dimethyl-2-hydroxymethyl-9H-dibenzo[b,f]-imidazo[1,2-d] [1,4]diazepine is suspended in a chloroform/tetrahydrofuran mixture and treated with triethylamine. After cooling to -20° C. methanesulfonyl chloride is added with stirring at -20° C. The mixture is treated with 4-methylpiperazine and warmed gradually to room temperature. Work-up from an aqueous base followed by the usal purification techniques affords the product 3,9-dimethyl-2-(4-methyl-1-piperazinyl)methyl-9H-dibenz[b,f]-imidazo[1,2-d][1,4]diazepine as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.C(N(CC)CC)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:14][CH2:15][C@H:16]([NH:19][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:17][CH2:18]2)[CH2:9][CH2:8]1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@H]1CC[C@H](N2CCN(c3ccccn3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](N2CCN(c3ccccn3)CC2)CC1)c1ccccc1

Procedure:
To a solution of 5.8 g trans-4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexylamine (Example 31a) in 100 mL of dichloromethane is added 4 mL of triethylamine and 2.84 mL of benzoyl chloride. The reaction mixture is refluxed under nitrogen for 1 hour. Saturated sodium bicarbonate solution is added. Some of the product comes out of solution at this point and is isolated by filtration. The organic layer is dried and evaporated to give 5.2 g of trans-N-[4-[4-(2-pyridinyl)-1-piperazinyl]cyclohexyl]benzamide; mp 241-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:12]([Cl:11])[CH:13]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: OCc1ccc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.4 %

Procedure:
2-Chloro-4-hydroxybenzaldehyde (324 mg, 2.07 mmol), 3,4-dichlorobenzyl alcohol (513 mg, 2.90 mmol), and triphenylphosphine (760 mg, 2.90 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.32 mL, 2.90 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was washed with hexane/dichloromethane (6/1 (v/v)), whereby the objective title compound was obtained as a white solid (244 mg, yield: 37%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([O-])(O)=O.[Na+].[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]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>[Cl:9][C:4]1[CH:5]=[C:6]([C:17]2[O:18][C:19]([CH3:10])=[CH:15][CH:16]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=C([O-])O
Reactant: C1CCOC1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: Cc1ccc(-c2cc(Cl)nc(N)n2)o1
Yield: 96 %

Procedure:
A solution of 2-methylfuran (11 mL, 122 mmol) and N,N,N′,N′-tetramethylethylenediamine (18.4 mL, 122 mmol) in anhydrous THF (500 mL) at −78° C. under nitrogen was treated with n-butyl lithium (48.8 mL, 122 mmol), stirred at −78° C. for 20 min, warmed to 0° C. for 30 min and then warmed to room temperature for 15 min. The reaction was cooled to −78° C., treated with trimethyl borate (27.4 ml, 244 mmol), warmed to room temperature, treated with MeOH (100 mL) and water (5 mL), stirred at room temperature for 30 min and concentrated in vacuo. The residue was treated with MeOH (3×100 mL) and concentrated in vacuo after each addition to give the boronic ester as an orange gum. A solution of 2-amino-4,6-dichloropyrimidine (20 g, 122 mmol) in THF (1 L) was treated with saturated aqueous NaHCO3 (250 mL), a solution of the above boronic ester (122 mmol) in THF (50 mL) and tetrakis(triphenylphosphine)palladium (6.93 g, 6 mmol), stirred at 70° C. for 20 h, cooled, extracted with EtOAc (2×100 mL), washed with water (200 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo to give the product (24.5 g, 96%) as a yellow solid; NMR δH (400 MHz, DMSO) 2.37 (3H, s), 6.32-6.33 (1H, m), 6.89 (1H, s), 7.11 (2H, s) and 7.18-7.19 (1H, m).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].CI.[CH2:25](OCC)C>CN(C)C=O>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH:13]([O:15][CH3:25])[CH2:14][N:10]1[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1CN(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
At 0°-5° C., 1.2 g of a sodium hydride dispersion (80 %) are added in portions to a solution of 8.6 g of 4-hydroxy-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester in 90 ml of N,N-dimethylformamide. After stiffing for 30 minutes at 0°-5° C., a solution of 2.5 ml of methyl iodide in 10 ml of N,N-dimethylformamide is added dropwise thereto. Stirring is then continued for 3 hours at 0°-5° C. and then 500 ml of diethyl ether are added thereto. The organic phase is washed with water, dried over sodium sulfate and concentrated to yield 8.0 g of the desired product, 4-methoxy-pyrazolidine-N,N'-dicarboxylic acid di-tertbutyl ester, in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](O)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=1.[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([NH:43][CH3:44])[CH2:39][CH2:38]1.ON1C2C=CC=CC=2N=N1.[ClH:55].CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:55][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([Cl:14])=[CH:12][C:11]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([N:43]([CH3:44])[CH:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[C:10]([O:34][CH3:35])[CH:9]=1
Reactant: Cl
Reactant: CNC1CCN(C)CC1
Reactant: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2ccccc2Cl)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)C3CCN(C)CC3)n2Cc2ccccc21
Reaction time: 8 h
Yield: 33 %

Procedure:
To a stirred solution of 10-{[2′-chloro-6-chloro-3-methoxy-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 16, Step C (0.250 g, 0.49 mmol) was added 1-methyl-4-(methylamino)piperidine (0.076 g, 0.59 mmol) followed by 1-hydroxybenzotriazole (0.073 g, 0.54 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.093 g, 0.54 mmol), and N,N-diisopropylethyl amine (0.096 g, 0.74 mmol). After stirring overnight, the reaction mixture was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was flash chromatographed over silica gel eluting with 5% methanol in chloroform containing 0.5% ammonium hydroxide, to provide the title compound as white powder (0.100 g), 92.95% pure by analytical HPLC [Primesphere C-18 column (2.0×150 mm); mobile phase:gradient from 10 to 90% acetonitrile/water containing 0.1% phosphoric acid, 2 to 20 minute gradient].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH2:18])=[C:12]2[N:11]=[C:10]1[CH3:20].C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2=[N:14][C:15]([CH3:19])=[CH:16][C:17]([NH:18][C:32](=[O:33])[CH2:31][Cl:30])=[C:12]2[N:11]=[C:10]1[CH3:20]
Reactant: Cc1cc(N)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(NC(=O)CCl)c2nc(C)n(-c3ccc(Cl)cc3Cl)c2n1
Temperature: 25 °C

Procedure:
Treat a solution of 3-(2,4-dichlorophenyl)-2,5-dimethylimidazolo[5,4-b]pyridin-7-ylamine (0.2 g, 0.65 mmol), and N,N-diisopropylethylamine, (0.12 mL, 0.72 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.06 mL, 30.72 mmol). Heat the solution to reflux for 2 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter, and concentrate. Purify by preparative TLC (5% methanol in CH2Cl2) to obtain the title compound as a yellow solid.