Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:40][CH2:39][C:12]2[N:13]=[C:14]([NH:16][C:17](=[O:38])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH:29]=[C:28]([C:30]5[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=5)[N:27]=[N:26]4)[CH:19]=3)[S:15][C:11]=2[CH2:10]1.[CH3:41][O:42][CH2:43][CH2:44]Br.C(N(CC)CC)C.[I-].[Na+]>CCO>[C:36]([C:33]1[CH:32]=[CH:31][C:30]([C:28]2[N:27]=[N:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:14]3[S:15][C:11]4[CH2:10][C@H:9]([NH:8][CH2:44][CH2:43][O:42][CH3:41])[CH2:40][CH2:39][C:12]=4[N:13]=3)=[O:38])[CH:29]=2)=[CH:35][CH:34]=1)#[N:37]
Reactant: COCCBr
Reactant: N#Cc1ccc(-c2cn(Cc3cccc(C(=O)Nc4nc5c(s4)C[C@H](N)CC5)c3)nn2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCCN[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1
Temperature: 110 °C
Yield: 38.7 %

Procedure:
Add to a solution of N—((R)-6-amino-4,5,6,7-tetrahydro-benzothiazol-2-yl)-3-[4-(4-cyano-phenyl)-1,2,3-triazol-1-ylmethyl]-benzamide trifluoroacetate (0.92 g, 1.61 mmol), bromoethyl methyl ether (0.22 g, 1.61 mmol), triethylamine (0.33 g, 3.22 mmol) and sodium iodide (0.02 mg, 0.16 mmol) in 8 mL of EtOH. Heat the reaction mixture at 110° C. under microwave irradiation for 5 h. Filter the mixture, concentrate and purify via preparative HPLC to give 0.32 g, 39% yield of 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-N—[(R)-6-(2-methoxy-ethylamino)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-benzamide as white foam. MS, ES+ 514.45 (M+H), rt 5.27 min
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(OP(Cl)(OCC)=O)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH:45]=O)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([CH:22]=[CH:45][CH:42]3[CH2:43][CH2:44][N:39]([C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:38])[CH2:40][CH2:41]3)(=[O:20])=[O:21])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (8.6 ml of a 1.6 M solution in THF) was added dropwise to a suspension of 4-(4-fluorophenyl)-1-methanesulphonylpiperazine (3.52 g) in THF (40 ml) at −78° C. and the mixture was stirred for 30 minutes. Diethylchlorophosphate (1.97 ml) was added dropwise and the mixture was stirred at −78° C. for a further 30 minutes. n-Butyl lithium (8.6 ml of a 1.6 M solution in THF) was added dropwise and stirred for 30 minutes. A solution of 1-(t-butoxycarbonyl)-piperidine-4-aldehyde (2.91 g) in THF (5 ml) was added dropwise and the mixture was allowed to warm to ambient temperature and was stired for 10 hours. Saturated aqueous ammonium chloride solution (5 ml) was added, the reaction mixture was diluted with ethyl acetate (25 ml) and washed with water. Removal of the solvent gave 4-(4-fluorophenyl)-1-[2-(1-t-butoxycarbonylpiperidin-4-yl)-ethenylsulphonyl]-piperazine as a gum which solidified on standing, M+H=455 (454).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([N:36]([C:44](=[O:46])[CH3:45])[C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)[CH2:28][C@@H:27]3[CH3:47])=[O:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([N:36]([C@H:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([C:24](=[O:25])[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][CH2:14][N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:19][CH:20]=3)[C@@H:27]([CH3:47])[CH2:28]2)[C:44](=[O:46])[CH3:45])=[CH:38][CH:39]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCNCC3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(3-piperazin-1-yl-propoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide was prepared from (2S,4R)-4-[3-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester. (2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.40 g, 0.92 mmol) was dissolved in DMF at room temperature and K2CO3 (0.127 g, 0.921 mmol) was added. 4-(3-Chloro-propyl)-piperazine-1-carboxylic acid tert-butyl ester (0.242 g, 0.921 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography to afford the product as colorless oil in 50% yield. (2S,4R)-4-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-piperazine-1-carboxylic acid tert-butyl ester (246 mg) was dissolved in 4M HCl in dioxane (2 mL). The mixture was stirred for 2 h at room temperature. After concentration, the white solid was washed with EtOAc to provide the title compound in 100% yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([N+:23]([O-])=O)=[C:8]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[CH:9]=2)[CH2:3][CH2:2]1.[Sn](Cl)Cl.Cl>C(O)C>[CH:1]1([C:4]2[CH:9]=[C:8]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:7]([NH2:23])=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1ccc(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C2CC2)cc1NC1CCN(C2CCOCC2)CC1
Reaction time: 18 h

Procedure:
A stirred mixture of N-(5-cyclopropyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D44, 150 mg, 0.43 mmol) and tin (II) chloride (326 mg, 1.72 mmol) in ethanol (10 ml) was treated with conc. HCl acid (˜0.38 ml) and heated at reflux temperature with stirring for 18 hrs. The solvent was removed by concentration under vacuum and the residue treated with dilute K2CO3 solution and extracted with ethyl acetate, filtering the mixture to remove tin residues. The separated organic phase was washed with water and brine, dried (MgSO4) and concentrated under vacuum to afford the title compound as a very pale brown sticky gum (114 mg, 83%). M++H=316.1.
Reaction SMILES: [OH:1][CH:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][CH2:5]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.[OH-].[Na+]>C(Cl)(Cl)Cl>[OH:1][CH:2]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([NH:10][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:5]1
Reactant: NN1CCN(CC(O)c2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NN1CCN(CC(O)c2c[nH]c3ccccc23)CC1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 8.60 g (0.0334 mol) of 3-[1-hydroxy-2-(4aminopiperazin-1-yl)ethyl]indole in 50 ml. of chloroform is added 4.55 g (0.045 mol) of triethylamine. The mixture is cooled to 0° C. under a nitrogen atmosphere, and a solution of 5.64 g (0.040 mol) benzoyl chloride in 10 ml. of chloroform is introduced dropwise for 1 hour, while maintaining the reaction temperature of 0°-5° C. The resulting mixture is stirred at 0° C. for one hour, and at ambient temperature for another hour. The mixture is diluted with 150 ml. of chloroform and then 100 ml. of 10% sodium hydroxide. This mixture is stirred for 15 minutes and then filtered; the cake is washed well with water and dried to give a white solid. This product is recrystallized first from an ethanol and water mixture and then twice from DMF and water to give pure white crystals of 3-[1-hydroxy-2-(4-benzamidopiperazin-1-yl)ethyl]indole, m.p. 211°-213° C. dec. Analysis: Calculated for C21H24N4 02 : 69.21% C; 6.64% H; 15.37% N Found: 69.00% C; 6.60% H; 15.28% N.
Reaction SMILES: CN(C)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O.[CH:18]1[CH:19]=[CH:20][N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]=12.O.O.O.C([O-])(=O)C.[Na+]>O.ClCCCl>[F:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([C:20]2[N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[C:22]3=[CH:18][CH:19]=2)=[O:11])=[CH:9][CH:8]=1
Reactant: CN(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)OC(=O)C1CCCn2cccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: CC(C)OC(=O)C1CCCn2c(C(=O)c3ccc(F)cc3)ccc21

Procedure:
A solution of 758 mg. of N,N-dimethyl-4-fluorobenzamide and 0.44 ml. of phosphorous oxychloride in 50 ml. of 1,2-dichloroethane is refluxed for one hour. To this solution is added a solution of 500 mg. of isopropyl 5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate in 10 ml. 1,2-dichloroethane. The reaction mixture is refluxed for 3 hours. A solution of 3.3 g. sodium acetate trihydrate in 9 ml water is added and refluxed for a further 10 hours. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is purified by preparative t.l.c. using hexane:ethyl acetate (90:10). Crystallization from dichloromethane-hexane yields isopropyl 3-p-fluorobenzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate (XI, R=H, L=p-F, R2 =iC3H7, n=1), m.p. 92° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[O]N(S(=O)([O-])=O)S(=O)([O-])=[O:21].[K+].[K+].Cl>[OH-].[Na+]>[CH3:8][C:7]1[C:2](=[O:1])[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH3:10])[C:5](=[O:21])[C:6]=1[CH3:9]
Reactant: Cc1cc(C)c(CCCCCCO)c(O)c1C
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: CC1=C(C)C(=O)C(CCCCCCO)=C(C)C1=O
Temperature: 0 °C

Procedure:
To a solution of 6-(2'-hydroxy-3',4',6'-trimethylphenyl)hexanol (formula III-2, wherein R=H3C, X=H, Y=OH, n=4, in the free form) (0.02 part) in 1% sodium hydroxide solution (25 parts) was added Fremy's salt (0.2 part) at room temperature with stirring. After being stirred for 1 hour, the mixture was cooled to 0° C., acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give 2,3,5-trimethyl-6-(6'-hydroxyhexyl)-1,4-benzoquinone (formula IV-2 wherein R=H3C, n=4, in the free form) (0.02 part) as yellow needles melting at 43°-45° C.
Reaction SMILES: [CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH:40]1([C:46]([OH:48])=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][CH:2]1[CH:27]2[O:28][C:26]2([CH3:29])[CH:25]([OH:30])[CH2:24][C:22](=[O:23])[N:21]([CH3:31])[C:14]2=[C:15]([Cl:20])[C:16]([O:18][CH3:19])=[CH:17][C:12](=[CH:13]2)[CH2:11][C:10]([CH3:32])=[CH:9][CH:8]=[CH:7][CH:6]([O:33][CH3:34])[C:5]2([OH:39])[NH:35][C:36]([O:38][CH:3]1[CH2:4]2)=[O:37].[CH2:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:46]([O-:48])=[O:47])[CH2:41]1
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: COc1cc2cc(c1Cl)N(C)C(=O)CC(O)C1(C)OC1C(C)C1CC(O)(NC(=O)O1)C(OC)/C=C/C=C(\C)C2
Solvent: ClCCl
Product: O=C([O-])C1CCCCC1
Temperature: 25 °C

Procedure:
In 5 ml of dry dichloromethane are dissolved maytansinol (103.2 mg, 0.183 mmol) and cyclohexanecarboxylic acid (140 mg, 1.094 mmols), followed by addition of dicyclohexylcarbodiimide (DCC) (267 mg, 1.296 mmols). The mixture is stirred at room temperature for a while until insolubles have begun to separate out. Then, after addition of p-dimethylaminopyridine (DMAP) (50.8 mg, 0.416 mmol), the reaction mixture is stirred at room temperature overnight. The insolubles are filtered off, the filtrate is washed with 0.5 N HCl (ca. 10 ml) and saturated aqueous sodium hydrogen carbonate (ca. 10 ml) in that order and dried over anhydrous sodium sulfate. After the solvent is distilled off, the residue is chromatographed on a column of silica gel (75 g) and elution is carried out with ethyl acetate, the eluate being collected in 16-g fractions. Fractions 14 through 30 are pooled and the solvent is distilled off to recover 59 mg of crude product. This crude product is dissolved in ethyl acetate, followed by addition of ether, whereby 24.3 mg of maytansinol 3-cyclohexanecarboxylate is obtained as crystals melting at 202°-206° C. (decompn.)
Reaction SMILES: [CH:1]([O:4][C:5](=[O:41])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([C:10]4[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=4)[O:7][CH2:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:41])[N:23]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CC(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)OC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-(2-isopropoxy-2-oxoethoxy)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.26 mmol) in 1,4-dioxane (0.5 mL) was added a 4M solution of hydrogen chloride in 1,4-dioxane (3 mL) and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo residue was purified using prep HPLC (method 10-35—90 mins) to afford isopropyl 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetate. (28 mg, 0.062 mmol, 24%)
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[O:6][C:7]([F:10])([F:9])[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[C:20]#[CH:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CC#N.CC#N.Cl[Pd]Cl.O.C(#N)C>[F:9][C:7]1([F:10])[O:6][C:5]2[CH:11]=[CH:12][C:2]([C:21]#[C:20][CH2:19][O:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)=[CH:3][C:4]=2[O:8]1
Reactant: C#CCOC1CCCCO1
Reactant: FC1(F)Oc2ccc(Br)cc2O1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: FC1(F)Oc2ccc(C#CCOC3CCCCO3)cc2O1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of 5-bromo-2,2-difluoro-1,3-benzodioxole (10.0 g), cesium carbonate (35.0 g), 2-(2-propynyloxy)tetrahydropyran (8.90 ml), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.24 g), bis(acetonitrile)palladium(II) dichloride (219 mg) and acetonitrile (100 ml) was stirred at 90° C. for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (6.53 g) as a brown oil.
Reaction SMILES: CC(C)([O-])C.[K+].CO[C:9](=[O:21])[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O.[CH3:22][N:23]([CH2:25][C:26]1[CH:34]=[CH:33][C:32]2[N:28]([C:29]([CH2:36][C:37]([NH2:39])=[O:38])=[C:30]([CH3:35])[CH:31]=2)[CH:27]=1)[CH3:24].[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[CH3:22][N:23]([CH2:25][C:26]1[CH:34]=[CH:33][C:32]2[N:28]([C:29]([C:36]3[C:37](=[O:38])[NH:39][C:9](=[O:21])[C:10]=3[C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[C:30]([CH3:35])[CH:31]=2)[CH:27]=1)[CH3:24]
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: Cc1cc2ccc(CN(C)C)cn2c1CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc2ccc(CN(C)C)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.3 %

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.24 ml, 0.24 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of (1H-indol-3-yl)-oxo-acetic acid methyl ester (19.2 mg, 0.090 mmol, 1.1 equiv) and of 2-(6-dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetamide (20 mg, 0.08 mmol) in anhydrous tetrahydrofuran (1.0 ml, dried over molecular sieves). The reaction mixture is stirred for 30 minutes at room temperature. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via preparative HPLC affords the title compound (2 mg, 6%) as its trifluoroacetate salt. 1H NMR (400 MHz, d6-DMSO): δ=11.78 (s, 1H), 10.91 (s, 1H), 9.51 (s, 1H), 8.33 (s, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.54 (s, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 6.95 (dt, J=8.0/1.2 Hz, 1H), 6.61 (dd, J=9.3/1.3 Hz, 1H), 6.52 (dt, J=8.1/1.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 4.13 (s, 2H), 2.67 (s, 6H), 1.93 (s, 3H). MS (ES+): 399 (M+H)+.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]([CH3:37])[C:30]5[C:35]([CH:36]=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:27])=[C:21]([O:38][CH3:39])[CH:20]=3)=[CH:17][S:18][C:14]=2[C:13]([N:40]=[C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:12][N:11]=1>CN(C)C=O>[CH3:3][N:4]([CH:6]=[N:9][C:10]1[C:15]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]4[N:29]([CH3:37])[C:30]5[C:35]([CH:36]=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:27])=[C:21]([O:38][CH3:39])[CH:20]=3)=[CH:17][S:18][C:14]=2[C:13]([N:40]=[C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:12][N:11]=1)[CH3:5]
Reactant: COC(OC)N(C)C
Reactant: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(N=C(c4ccccc4)c4ccccc4)cnc(N=CN(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 95 °C
Reaction time: 9 h
Yield: 93.4 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (0.116 mL, 0.87 mmol) was added to a solution of N-(4-{4-amino-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.156 g, 0.257 mmol) in N,N-dimethylformamide (6 mL). The solution was stirred at 95° C. for 9 h, then was cooled to ambient temperature, and the mixture was concentrated. Partial purification of the residue by flash column chromatography on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used), using dichloromethane as the mobile phase afforded crude N-(4-{4-{[(dimethylamino)methylene]amino}-7-[(diphenylmethylene)amino]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide as a yellow foam (0.16 g, 0.24 mmol): MS: (MH)+ 663.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32].Cl>C(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cl
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2
Yield: 67.6 %

Procedure:
A mixture of 0.30 g (0.99 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 0.20 g (1.19 mmole) of 4-amino-3-methoxy-benzoic acid in a 1:4 mixture of 5 mL of ethanol and 1M hydrochloric acid was heated at 100 degrees for 18 hours. After cooling, the precipitate was collected by filtration, washed with water and dried to give 0.29 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-151).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:15]=[CH:14][N:13]=[CH:12]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:10]
Reactant: NCCCCn1ccnc1
Reactant: O=C=Nc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NCCCCn1ccnc1)Nc1ccccc1Cl

Procedure:
A solution of 2.30 g. of o-chlorophenyl isocyanate in 30 ml. of toluene was added with stirring to a solution of 2.09 g. of 1H-imidazole-1-butanamine in 20 ml. of toluene and the mixture was allowed to stir overnight and them evaporates to a crystalline residue. The crystals were dissolved in methylene chloride and purified by HPLC (silica gel column, eluted with 10% ethanol/ethyl acetate) to obtain the desired compound, mp. 87°-88° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:9](Br)Br)=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1.CC[OH:14]>O.[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[C:3]([CH:9]=[O:14])=[N:4][C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)c(C(Br)Br)n1
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1nc(Br)ccc1Br
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A solution of silver nitrate (8.5 g, 50 mmol) in water (26 mL) was added dropwise to a solution of compound 84 (8.17 g, 20 mmol) in refluxing EtOH (100 mL). The mixture was stirred at 80° C. for 5 hours. After the mixture was cooled to room temperature, it was diluted with water (100 mL), extracted with EtOAc (3×), dried over Na2SO4, filtered and concentrated under reduced pressure. The product was obtained after silica gel chromatography eluting with 0-40% EtOAc in hexane (2.85 g, 51% over two steps).
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3]1.[N+:26]([O-])([OH:28])=[O:27].N>S(=O)(=O)(O)O>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[C:9]([N+:26]([O-:28])=[O:27])[CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][C@H:4]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4c3C(CN4)C[C@H]2N(C)C1
Agent: N
Agent: O=S(=O)(O)O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc([N+](=O)[O-])cc4c3C(CN4)C[C@H]2N(C)C1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Under ice cooling, 10 mmol of 3-(2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea is dissolved in 100 ml of concentrated sulfuric acid; 7 ml of a solution of 10 ml of 65% nitric acid in 90 ml of concentrated sulfuric acid is added thereto, and the mixture is stirred for 15 minutes in an ice bath. The reaction solution is then slowly introduced dropwise into ice, made alkaline under ice cooling with 32% ammonia solution, and extracted by shaking with methylene chloride. After washing the organic phase with water and drying with magnesium sulfate, the nitrated compound is obtained in a 90% crude yield. After chromatographic separation and purification, respectively, 3-(2,3-dihydro-6-methyl-13-nitro-8α-ergolinyl)-1,1-diethylurea is obtained in a 71% yield.