Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].Br[CH2:52][C:53]1[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57]>>[CH3:41][O:40][C:38]([C:37]1[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])[CH2:4][CH2:3][N:2]([CH2:52][C:53]3[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=3)[C:56]([O:58][CH3:59])=[O:57])[CH3:1])=[O:16])=[O:24])=[CH:27][CH:28]=2)=[CH:43][CH:42]=1)=[O:39]
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: CCC(CC)N(CCN(C)Cc1cccc(C(=O)OC)c1)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Yield: 90.7 %

Procedure:
By using 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 79 mg of methyl 3-(bromomethyl)benzoate, the reaction similar to Preparation Example 30 was performed, thereby obtaining 220 mg of methyl 3-{[(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)(methyl)amino]methyl}benzoate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH:55]([C:58]1[O:62][N:61]=[CH:60][C:59]=1[C:63](O)=[O:64])([CH3:57])[CH3:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([C:59]2[CH:60]=[N:61][O:62][C:58]=2[CH:55]([CH3:57])[CH3:56])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: CC(C)c1oncc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1oncc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 18 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 5-isopropylisoxazole-4-carboxylic acid as starting materials in 18% yield. LCMS for C31H34ClN8O3 (M+H)+: m/z=601.2.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[N:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[O:34])=[C:28]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][C:43]4=[O:47])[CH:27]=3)=[CH:21][CH:20]=2)[N:15]=1>>[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[N:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][C:43]4=[O:47])[C:29]([NH:32][C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[O:34])=[C:30]([N+:1]([O-:4])=[O:2])[CH:31]=3)=[CH:21][CH:20]=2)[N:15]=1
Reactant: Cc1nc(-c2ccc(Oc3ccc(NC(=O)c4ccccn4)c(CN4CCCC4=O)c3)cn2)no1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2ccc(Oc3cc(CN4CCCC4=O)c(NC(=O)c4ccccn4)c([N+](=O)[O-])c3)cn2)no1
Temperature: 80 °C
Yield: 95.2 %

Procedure:
126 mg of potassium nitrate was added to a trifluoroacetic acid (3 ml) solution of 117 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide, and stirred under heat at 80° C. for 7 hours. Trifluoroacetic acid was evaporated away under reduced pressure, then chloroform was added to the residue, and washed with aqueous saturated sodium hydrogencarbonate solution. The organic layer was dried, and the solvent was evaporated away under reduced pressure to obtain 122 mg of N-{4-{[6-(5-methyl-1,2,4-oxadiazol-3-yl)pyridin-3-yl]oxy}-2-nitro-6-[(2-oxopyrrolidin-1-yl)methyl]phenyl}pyridine-2-carboxamide as a brown oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:28]=[CH:27][C:17]([C:18]([NH:20][C@@H:21]([CH:24]([CH3:26])[CH3:25])[CH2:22][OH:23])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(Cl)(Cl)=O>C(=O)([O-])[O-].[K+].[K+]>[CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]3[O:23][CH2:22][C@H:21]([CH:24]([CH3:25])[CH3:26])[N:20]=3)=[CH:27][CH:28]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[C@H]1CC[C@H](c2ccc(C(=O)N[C@H](CO)C(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CCCCCCC[C@H]1CC[C@H](c2ccc(C3=N[C@@H](C(C)C)CO3)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 1.05 g of 4-(trans-4-heptylcyclohexyl)-N-[(S)-2-hydroxy-1-isopropylethyl)benzamide in 40 ml of acetenitrile was treated dropwise with 0.7 ml of thionyl chloride at 0° C. and while gassing with nitrogen. The reaction mixture was stirred at 0° C. overnight, poured into 100 ml of saturated potassium carbonate solution and then extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 50 ml of saturated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 2:1) and recrystallization from acetone at -25° C. gave pure (S)-2-[4-(trans-4-heptylcyclohexyl)phenyl]-4-isopropyl-2-oxazoline with m.p. (C-I) 51° C. and cl.p. (S-I) 46° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20]>CC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH2:18][C:19]([OH:21])=[O:20])=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCC(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
The mixture of 2-fluoro-4-hydroxybenzonitrile (274 mg, 2.1 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 6 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 1, and then extracted three times with ethyl acetate (20 ml each). Organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol and petroleum ether to give 268 mg 4-cyano-3-fluorophenoxyacetic acid as white crystals, mp 150-152° C.
Reaction SMILES: C(OC([N:8]([C@@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([F:29])=[CH:21][N:22]=[C:23]([Cl:28])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=[O:42])C=2C(F)=CN=1.C(OC(N([C@@H]1CCNC1)C)=O)(C)(C)C.ClC1C2C=CC=C(S(Cl)(=O)=O)C=2C(Br)=CN=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[OH:42][C:23]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@@H:10]([NH:8][CH3:9])[CH2:11]3)(=[O:17])=[O:16])[C:19]=2[C:20]([F:29])=[CH:21][N:22]=1.[ClH:28]
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)ncc(F)c12
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(F)c23)C1
Agent: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2c(Cl)ncc(Br)c12
Product: CN[C@@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(F)c23)C1
Product: Cl

Procedure:
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(1-chloro-4-fluoro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 27b) can be prepared by using 1-chloro-4-fluoro-5-isoquinolinesulfonyl chloride and (R)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 35-1, Step A instead of 1-chloro-4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 35-1, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: C(OC([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([NH2:32])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18]>>[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([NH:32][C:10]([C@@H:9]3[CH2:13][C:14](=[CH2:16])[CH2:15][NH:8]3)=[O:12])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=C1CN[C@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 71% purity by LC/MS. MS(ESI+): m/z=320.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.[CH:28](I)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:27][CH:22]([C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:5]3[C:6]([O:8][CH:28]([CH3:30])[CH3:29])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[CH2:19][O:18][C:16](=[O:17])[C:15]=2[C:14]=1[O:20][CH3:21])[CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: CC(C)I
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(OC(C)C)c1O2

Procedure:
200 mg (0.54 mmol) of penicillide (Ib) in 2 ml of dimethylformamide are stirred under argon at 25° C. for 12 h with 0.5 ml (50 mmol) of isopropyl iodide and 160 mg (1.14 mmol) of anhydrous potassium carbonate. After evaporating in vacuo, the residue is taken up with 1 N aqueous hydrochloric acid and the mixture is exhaustively extracted with diethyl ether. After drying the organic phase, the evaporation residue is chromatographed on silica using petroleum ether/ether =1/1. Fractions which are pure by thin layer chromatography are combined and evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]3[CH2:16][CH2:15][CH2:14][CH:9]3[NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]2[N:8]3[CH2:16][CH2:15][CH2:14][C:9]3=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)NC1CCCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)S(=O)(=O)N=C1CCCN12
Temperature: 25 °C
Yield: 105.4 %

Procedure:
A stirred solution of 7-nitro-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (167 mg; 0.6 mmol) in dry THF (2 ml) at −50° C. was added LiAlH4 (115 mg; 3 mmol) in one portion. The reaction mixture was allowed to warm up to rt. and stirred over night. The reaction mixture was quenched by addition of H2O and 10 M NaOH, stirred, filtered through celite and evaporated to dryness to give 150 mg product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH2:4][CH2:3]1.[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]3)[N:11]=[C:10]([OH:20])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Reactant: COc1ccc(C=O)cc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(c3cc(O)nc(N4CCCCC4)n3)CC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A mixture of 6-Piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol, hydrochloride salt (2.0 mmol), 3-hydroxy-4-methoxy-benzaldehyde (2.6 mmol), triethylamine (4.0 mmol) and 3 drops of acetic acid in dry dichloromethane (20 mL) was stirred at room temperature for 3 hours. Then sodium triacetoxyborohydride (6.0 mmol) was added in portions and stirring was continued for 48 hours (monitored by TLC). The mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and the product was extracted with dichloromethane (2×10 mL). The extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded 6-[1-(3-hydroxy-4-methoxy-benzyl)-piperidin-4-yl]-2-piperidin-1-yl-pyrimidin-4-ol (Compound IIb, 542 mg, 68%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][N:8]([CH:9]([CH3:11])[CH3:10])[C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)NCc1ccc(C(F)(F)F)cc1
Product: CC(C)N(Cc1ccc(C(F)(F)F)cc1)C(=O)C(Cl)Cl
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of 21.7 g of N-(4-trifluoromethylbenzyl)-N-isopropyl-amine is added while stirring in a 4 neck-flask with 20 ml of 20% sodium-hydroxide solution. The reaction-mixture is then cooled while stirring in an alcohol/CO2 -bath to a temperature of from -10° to -5° whereupon 14.7 g of dichloroacetyl chloride is added slowly, dropwise thereto. After about 1/2 hour, when everything is added, the cooling-bath is removed and the reaction mixture is stirred for 2 hours until it reaches room temperature. It is then poured into ice/water and the organic material is extracted with toluene. The toluene-phases are collected washed first with diluted sodium hydroxide, then with diluted hydrochloric acid and eventually twice with water, dried over sodium sulfate and concentrated in a rotatory evaporator. A clear oil is thus obtained, which becomes solid after a while. The solid mass is then triturated with hexane and filtered to yield 21.7 g of crystalline N-(4-trifluoromethylbenzyl)-N-isopropyl-dichloroacetamide, melting at 92° to 93°.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15]1)(C1C=CC(C)=CC=1)(=O)=O.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])[CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[O:19]1[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16][CH2:15][CH:14]1[CH2:13][CH2:12][N:24]1[CH2:25][CH2:26][CH:27]([N:30]2[CH2:34][CH2:33][NH:32][C:31]2=[O:35])[CH2:28][CH2:29]1
Reactant: O=C1NCCN1C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1NCCN1C1CCN(CCC2COc3ccccc3O2)CC1

Procedure:
The mixture of 4.9 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 2.54 g of 1-(4-piperidyl)-2-imidazolidinone, 5 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 3 days. It is filtered, evaporated and the residue recrystallized from isopropanol, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone of the formula ##STR9## melting at 125°.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:17]([C:12]3[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=4)[N:11]=3)=[CH:18][CH:19]=[N:20]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 3-chloro-phenylhydrazine according to the method described for example 91. MS: M=415.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: COC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A suspension of 2.60 g (8.30 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 5A) in 46 ml of THF was treated slowly at −78° C. with 9.30 ml (9.30 mmol) of lithium hexamethyldisilylazide 1M in THF. After 20 min at −78° C., the mixture was warmed to nearly −10° C. to go entirely in solution and cooled to −78° C. just after. Then, a solution of 1.18 ml (12.45 mmol) of methyl bromoacetate in 15 ml of THF was added dropwise. Over night, the solution was naturally warmed to RT, poured on aqueous 10% KHSO4 solution and extracted with EtOAc(3×). The organic phase was dried (Na2SO4) and evaporated to give 3.21 g (quant.) of the titled compound as a light brown solid containing max 5% of methyl bromoacetate. MS: 385.3 (MH+, 2Cl).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O.[Li+].[I-]>N1C=CC=CC=1>[C:17]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 72 h
Yield: 29.2 %

Procedure:
To a solution of ethyl 3-amino-2-benzoyl-6-chloro-1H-indole-1-carboxylate (step 2 of Example 1, 200 mg, 0.58 mmol) in pyridine (5 ml) was added methanesufonyl chloride (0.07 ml, 0.87 mmol). After stirring for 72 h, the mixture was poured into water (100 ml) and extracted with diethyl ether (100 ml). The organic extract was washed consecutively with 10% aqueous citric acid (50 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml), and dried (MgSO4). After removal of solvent the residue (287 mg) was dissolved in DMF (5 ml) and LiI (362 mg, 2.7 mmol) was added. The mixture was heated at 120° C. for 5 h, cooled and partitioned between water (100 ml) and diethyl ether (100 ml). The organic layer was separated and washed with water (100 ml), brine (100 ml) and dried (MgSO4). After removal of solvent the residue was purified by flash chromatography eluting with ethyl acetate/hexane (1:4) to afford the title compound (59 mg, 29%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[OH:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH2:21])=[CH:16][CH:15]=1.P(Cl)(Cl)Cl>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([Br:11])[CH:10]=[C:2]([Br:1])[C:3]=3[OH:12])=[CH:19][CH:18]=2)=[CH2:21])=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc(Br)cc(Br)c1O
Reactant: C=C(c1ccc(N)cc1)c1ccc(Cl)cc1
Solvent: ClP(Cl)Cl
Product: C=C(c1ccc(Cl)cc1)c1ccc(NC(=O)c2cc(Br)cc(Br)c2O)cc1

Procedure:
Using the reaction conditions of Example 2, 5.92 g (0.02 mole) of 3,5-dibromosalicylic acid and 5.32 g (0.02 mole) of 1-(4-aminophenyl)-1-(4-chlorophenyl)ethylene in the presence of phosphorus trichloride were reacted to give 4.26 of purified N-[4-[1-(4-chlorophenyl)ethenyl]phenyl]-2-hydroxy-3,5-dibromobenzamide, m.p. 181°-183°.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=[O:18])[C:9]2=[CH:19][S:20][C:21]([CH3:22])=[C:8]12)=[O:6].[CH3:23][N:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[CH2:29][CH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(OCC)(=O)C.C(O)C>[CH3:22][C:21]1[S:20][CH:19]=[C:9]2[C:10](=[O:18])[NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:5]([NH:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][CH:32]([CH2:31][CH2:30][CH2:29][CH:25]4[CH2:26][CH2:27][CH2:28][N:24]4[CH3:23])[CH2:33][CH2:34]3)=[O:6])[C:8]=12
Reactant: Cc1scc2c1N(C(=O)NCCBr)c1ccccc1NC2=O
Reactant: CN1CCCC1CCCC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCC3CCCN3C)CC1)c1ccccc1NC2=O
Yield: 18 %

Procedure:
Prepared analogously to Example 109 from 4-[[[2-bromo-ethyl]amino]carbonyl]-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 4-[3-(1-methyl-pyrrolidin-2-yl)propyl]piperidine in a yield of 18% of theory. Colourless crystals, m.p. 145°-146° C. (from ethyl acetate/ethanol). RF =0.5 (TLC investigation as in Example 114).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH:19]C(=O)C)[CH2:9][C@@H:8]1[CH3:23])=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([NH2:19])[CH2:9][C@@H:8]1[CH3:23])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1ccc2c(n1)[C@H](NC(C)=O)C[C@H](C)N2C(=O)OC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc2c(n1)[C@H](N)C[C@H](C)N2C(=O)OC(C)C
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Heat at 80° C. a solution of (+/−)-cis-4-acetylamino-6-methoxy-2-methyl -3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (405 mg, 1.261 mmol) in 5 N HCl (3 mL) for 3 h. Cool the reaction mixture to room temperature, pour into a saturated solution of sodium carbonate, and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (0.315 g, 89%). MS (ES+): 280 (M+H).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>O.ClCCl>[Cl:7][C:8]1[C:13]2[CH2:14][NH:15][CH2:16][CH2:17][S:18](=[O:2])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cccc2c1CNCCS2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S1CCNCc2c(Cl)cccc21
Reaction time: 19 h

Procedure:
A solution of sodium periodate (3.09 g) in water (25 ml) was added dropwise with cooling to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (2.88 g, prepared in a similar manner to that described in the preceding paragraph) in dichloromethane (75 ml). The stirring was continued at room temperature for 19 hours. Solvent was removed from the mixture by evaporation at reduced pressure. Purification of the residue by flash chromatography using dichloromethane/ethanol (95:5) as eluent gave 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide, which was recrystallised from ethyl acetate. Yield 2.15 g (m.p. 125°-126° C.).