Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:5]([C:17]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[C:6]([C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:7]=1.[C:35]1([S:57](Cl)(=[O:59])=[O:58])[C:44]2[CH:43]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[CH:41]=[C:40]([S:49](Cl)(=[O:51])=[O:50])[C:39]=2[CH:38]=[C:37]([S:53](Cl)(=[O:55])=[O:54])[CH:36]=1>N1C=CC=CC=1>[C:35]1([S:57]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])[CH:3]=2)(=[O:59])=[O:58])[C:44]2[C:39](=[C:40]([S:49]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[O:9])[C:5]([C:17]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[C:4]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[CH:3]=3)(=[O:51])=[O:50])[CH:41]=[C:42]([S:45]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[O:9])[C:5]([C:17]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[C:4]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[CH:3]=3)(=[O:47])=[O:46])[CH:43]=2)[CH:38]=[C:37]([S:53]([NH:1][C:2]2[CH:7]=[C:6]([C:8]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])[C:5]([C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[C:4]([C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[CH:3]=2)(=[O:55])=[O:54])[CH:36]=1
Reactant: Nc1cc(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c(C(=O)Oc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)Cl)c2cc(S(=O)(=O)Cl)cc(S(=O)(=O)Cl)c2c1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1cc(NS(=O)(=O)c2cc(S(=O)(=O)Nc3cc(C(=O)Oc4ccccc4)c(C(=O)Oc4ccccc4)c(C(=O)Oc4ccccc4)c3)c3cc(S(=O)(=O)Nc4cc(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c4)cc(S(=O)(=O)Nc4cc(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c(C(=O)Oc5ccccc5)c4)c3c2)cc(C(=O)Oc2ccccc2)c1C(=O)Oc1ccccc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a solution of 36.27 g. of 5-amino-1,2,3-benzenetricarboxylic acid, triphenyl ester in 150 ml. of dry pyridine is added 12.0 g. of 1,3,5,7-naphthalenetetrasulfonyl chloride and the mixture is stirred at room temperature for one hour and then at 55°-75° C. for 2 hours. The solution is poured into 840 ml. of 2 N hydrochloric acid and the resulting mixture is extracted with methylene chloride. The aqueous phase is filtered to remove the suspended solid which is washed with water and methylene chloride to provide 32.4 g. of a cream powder. The product is crystallized from acetone-methylene chloride and is then refluxed in acetonitrile:methanol (2:1) solution. The product is filtered and the filtrate cooled to 5° C. to provide additional product. The combined fractions are dried overnight in an Abderhalden apparatus at 110° C. to give 21.45 g. of beige powder, mp. >300° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]=[C:12]=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:48])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][NH:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)=[CH:32][CH:31]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>ClCCl>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:48])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]2)[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[O:13])=[CH:32][CH:31]=1)=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: CN1CCN(CCCNCc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Product: CN1CCN(CCCN(Cc2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C(=O)Nc2ccc3c(c2)OCCO3)CC1
Yield: 94 %

Procedure:
2,3-Dihydrobenzo[1,4]dioxin-6-ylisocyanate (0.11 mL, 0.80 mmol) was added to a solution of N-(2-t-butoxycarbonylaminophenyl)-4-[3-(4-methylpiperazin-1-yl)propylaminomethyl]benzamide (Reference Compound No. 4-1, 350 mg, 0.73 mmol) in anhydrous dichloromethane (15 mL), and then the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-methanol) to give 460 mg of the title reference compound as a colorless amorphous product. (Yield 94%)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:10]2([O:15][C:14]3[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:13]=3[CH:12]=[CH:11]2)[N:9]([CH2:23][CH2:24][OH:25])[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(N(CC)CC)C.[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1([CH3:26])[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]([CH2:23][CH2:24][O:25][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:10]21[CH:11]=[CH:12][C:13]1[C:14](=[CH:16][CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)[O:15]2
Reactant: CC1(C)c2ccccc2N(CCO)C12C=Cc1cc([N+](=O)[O-])ccc1O2
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)c2ccccc2N(CCOC(=O)CCC(=O)O)C12C=Cc1cc([N+](=O)[O-])ccc1O2
Temperature: 25 °C
Reaction time: 19 h

Procedure:
About 2 g of 1-(2-Hydroxyethyl)-3,3-dimethylindolino-6′-nitrobenzopyrylospiran (TCI America), about 0.44 ml of triethylamine, and about 0.69 g of 4-(dimethylamino)pyridine were dissolved in about 30 ml of dichloromethane. After addition of about 0.59 g of succinic anhydride, the solution was stirred under Ar at room temperature for about 19 hours. The mixture was washed with 5% aqueous hydrochloric acid, aqueous sodium bicarbonate, and water, then dried over magnesium sulfate. After the solvent was distilled off, the concentrated solution was added dropwise to hexane under stirring. The resulting solid was collected by filtration to yield 4-(2-(3′,3′-dimethyl-6-nitrospiro[chromene-2,2′-indoline]-1′-yl)ethoxy)-4-oxobutanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: Br
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)cc(Br)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a suspension of 2-amino-3-chlorobenzoic acid (2 g, 11.6 mmol) in chloroform (120 mL) was added dropwise bromine (1.1 equiv.) in chloroform (12 mL) solution. The mixture was stirred at room temperature for 16 hrs. The resulting white solid was collected by filtration and washed thoroughly with methylene chloride until the filtrate was colorless. The solid was air-dried to give 3.35 g of white powder as HBr salt of 2-amino-5-bromo-3-chlorobenzoic acid (87% yield). ES/MS m/z 250/252 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O>[Si:35]([O:25][C@@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:26])[C@H:19]([CH2:18][C@@H:17]([OH:27])[C@@H:16]3[C@@H:15]2[CH2:14][C@H:13]([OH:28])[C@@:12]2([CH3:29])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[CH2:24]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 8 h

Procedure:
Cholic acid, 4.08 g, is dissolved in 10 ml of dry dimethylformamide and 3.40 g of imidazole is added, followed by 3.60 g of t-butyldimethylsilyl chloride. The reaction mixture is allowed to stand overnight at room temperature. The reaction mixture is poured into water, filtered and the precipitate is washed with water. This precipitate is dissolved in 30 ml of tetrahydrofuran and 3 ml of water and 2 ml of acetic acid is added. After 6.5 hours, the solvent is evaporated and the residue chromatographed on 200 g of silica gel with 5% methanol in methylene chloride as eluent, to provide 3α-(t-butyldimethylsilyloxy)-7α,12α-dihydroxy-5β-cholan-24-oic acid, mp 145.5°-148, having the following structural formula: ##STR15##
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5](F)=[CH:6][CH:7]=1.[CH3:17][O-:18].[Na+]>CO>[F:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][C:5]([O:18][CH3:17])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Fc1ccc(F)c(NCC2CCOCC2)n1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(F)c(NCC2CCOCC2)n1
Temperature: 25 °C

Procedure:
To a solution of 3,6-difluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (5 g, 21.91 mmol) in MeOH (35 mL) was added sodium methoxide (25 wt. % in MeOH, 15.03 mL, 65.7 mmol). The resulting mixture was heated in a steel bomb at about 135° C. for ˜18 hr. The mixture then was cooled to ambient temperature and concentrated in vacuo. The resulting residue was taken up in water (˜250 mL) yielding a precipitate, which was collected by filteration, and then washed with water. The solid then was dissolved in toluene (10 mL)/DCM (10 mL), decanted from the dark brownish film and concentrated in vacuo. The resulting residue was dried in high vacuo providing crude 3-fluoro-6-methoxy-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a nearly colorless oil, which was directly used in the next reaction without further purification. Yield: 4.96 g. LCMS (m/z): 241.1 [M+H]+; Retention time=0.87 min.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH2:22][S:23][CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][CH:21]=1)[CH3:14].[NH3:27]>>[CH3:14][N:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]2[C:7]([NH2:27])=[N:6][S:5](=[O:11])(=[O:10])[N:4]=2)[CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: N
Product: CN(C)Cc1cccc(CSCCNC2=NS(=O)(=O)N=C2N)c1

Procedure:
When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamine [prepared according to the procedure described in Belgian Pat. No. 867,106] and excess ammonia by the general procedure described in Example 35, the title compound is thereby produced.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:43])[CH:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[NH:28]C(OC(C)(C)C)=O)[C@H:21]3[S:20][CH2:19][C:18]=2[CH:44]=[N:45][O:46][CH3:47])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].C1(OC)C=CC=CC=1>CCOCC>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH3:47][O:46][N:45]=[CH:44][C:18]1[CH2:19][S:20][C@@H:21]2[CH:24]([NH:25][C:26](=[O:42])[CH:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH2:28])[C:23](=[O:43])[N:22]2[C:17]=1[C:15]([OH:16])=[O:14]
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2SC1
Reaction time: 0.42 h
Yield: 93.3 %

Procedure:
A solution of diphenylmethyl-3-methoxyiminomethyl-7-(N-tertiary butoxycarbonyl-α-phenylglycyl)amino-3-cephem-4-carboxylate (64 mg) in ice-cooled trifluoroacetic acid (0.6 ml) and anisole (0.3 ml) is kept at room temperature for 25 minutes, and diluted with ether (5 ml) and petroleum ether (15 ml). The resulting crystals are collected by filtration and dried to give 3-methoxyiminomethyl-7-(α-phenylglycyl)amino-3-cephem-4-carboxylic acid trifluoroacetate (46 mg; 93.3%). m.p. about 270° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:36]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[CH:35]=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:37])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: N[C@@H](CCO)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 82.3 %

Procedure:
(S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (2.055 g, 11.07 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (4 g, 11.07 mmol) and DIPEA (5.80 ml, 33.20 mmol) in DMA (40 ml). HATU (4.63 g, 12.18 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness and triturated with dioxane (40 ml) to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) as a white solid. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) was suspended in dioxane (40.0 ml) and 4M hydrogen chloride in dioxane (7.69 ml, 221.36 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (1.200 g, 25.3%) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:3]([N:5]([CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])=[O:4].[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([N:36]=[C:37]=[S:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[CH:7]([N:5]([CH3:6])[C:3](=[O:4])[C@@H:2]([NH:1][C:37]([NH:36][C:28]1[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:26]([C:25]([F:24])([F:39])[F:40])[CH:27]=1)=[S:38])[C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C(=O)[C@@H](N)C(C)(C)C)C(c1ccccc1)c1ccccc1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: CN(C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A 100-mL round-bottomed flask containing (S)-2-amino-N-benzhydryl-N,3,3-trimethylbutanamide (6b) (2.98 g, 9.60 mmol, 1.0 equiv) was charged with anhydrous CH2Cl2 (30 mL). 3,5-Bis(trifluoromethyl)phenylisothiocyanate (1.75 mL, 9.60 mmol, 1.0 equiv) was added in one portion via syringe. The flask was capped with a plastic stopper, and the reaction mixture was stirred for 2 h at room temperature. The clear, yellow solution was concentrated using a rotary evaporator. The residue was subjected to purification by flash column chromatography on silica gel (gradient elution, hexanes→1:1 hexanes/Et2O, 100 g silica gel, 1.5 L solvent). The product (4e) was isolated as a white solid in ˜98% 1H-NMR purity (5.14 g, 8.83 mmol, 92% yield; 74% yield over three steps). The compound exists as a 15:1 mixture of amide rotamers in CDCl3. [α]=−83.4° (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3), major rotamer: δ 8.26 (1H, br s), 8.92 (1H, br s), 7.69 (2H, s), 7.59 (1H, s), 7.31-7.37 (3H, m), 7.13-7.16 (2H, m), 6.95-7.06 (5H, m), 5.65 (1H, d, J=9 Hz), 3.13 (3H, s), 1.13 (9H, s); selected minor rotamer resonances: δ 2.76 (3H, s), 0.92 (9H, s). 13C {1H} NMR, major rotamer: δ 182.5, 174.2, 139.7, 139.0, 137.3, 131.9 (q, JC-F=34 Hz), 129.8, 128.8, 128.7, 128.4, 128.2, 127.5, 127.2, 126.3 (m), 123.1 (q, JC-F=274 Hz), 119.3 (m), 62.4, 62.3, 36.5, 34.0, 27.6. IR (cm−1): 3313 (br m), 2967 (m), 1609 (m), 1529 (m), 1473 (m), 1380 (m), 1276 (s), 1172 (m), 1127 (s), 961 (m), 889 (w), 847 (w), 758 (w), 698 (m), 681 (m). LRMS (ESI): 582.2 (80%) [M+H].
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([CH3:11])[CH:4]=1)=[O:2].[CH2:12]([O:14][C:15](=[O:18])[CH2:16]Cl)[CH3:13].CC[O-].[Na+].O>C1C=CC=CC=1.C(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[O:2][CH:16]2[C:15]([O:14][CH2:12][CH3:13])=[O:18])=[CH:4][C:5]=1[CH3:11])#[N:8]
Reactant: Cc1cc(C=O)ccc1C#N
Reactant: CCOC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1OC1c1ccc(C#N)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-formyl-2-methylbenzonitrile (1.5 g, 10.3 mmol) and chloroacetic acid ethyl ester (1.2 g, 10 mmol) were dissolved in 60 mL of dry benzene. Freshly prepared EtONa (12.4 mmol) in 5 mL of ethanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was added water, then extracted with EtOAc. The organic layers were dried over Na2SO4 and concentrated to afford ethyl 3-(4-cyano-3-methylphenyl)oxirane-2-carboxylate. MS m/z: 232 (M+1)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Cl:13])[CH:12]=1)[CH2:9][N:8]([CH3:14])[CH2:7][CH:6]2[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C>C(Cl)Cl>[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:6]2[C:5]3[C:10](=[C:11]([Cl:13])[CH:12]=[C:3]([Cl:2])[CH:4]=3)[CH2:9][N:8]([CH3:14])[CH2:7]2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: NCCOCCOCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride hydrochloride (intermediate 10.6) (9 g, 20.02 mmol, 1.00 equiv, 95%) in DCM (200 mL) was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (15.6 g, 105.41 mmol, 5.00 equiv) and triethylamine (4.26 g, 42.18 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was diluted with 100 mL of DCM and then washed with 2×50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (10:1). This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32].[CH3:33][NH2:34].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CI)C(O)C3O)c2n1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CNC)C(O)C3O)c2n1
Reaction time: 18 h

Procedure:
A solution of the product from step (c) (0.25 g) in dimethylsulphoxide (3mil) was treated with a 40% solution of aqueous methylamine (1 ml). The reaction mixture was allowed to stand for 18 hours at room temperature then poured into ethyl acetate (200 ml), washed with a saturated solution of aqueous brine (3×100 ml), dried and concentrated. Purification (SiO2, methanol:chloroform 1:4 as eluant) afforded the subtitle compound (0.27 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([S:43][CH3:44])[C:14]=1[C:15]([NH:17][C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]([O:24]COC)[CH2:21][N:20]([CH3:28])[CH2:19]1)=[O:16].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:38]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:36]=[C:35]([S:43][CH3:44])[C:14]=1[C:15]([NH:17][C:18]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][C:22](=[O:24])[CH2:21][N:20]([CH3:28])[CH2:19]1)=[O:16]
Reactant: COCOC1CN(C)CC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2SC)(c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CC(=O)CN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a −50° C. solution of 11 ul (0.21 mmol) oxalyl chloride in 0.8 ml dichloromethane was added a solution of 17.2 ul DMSO in 0.2 ml dichloromethane over a period of 15 minutes. The reaction mixture was stirred for 10 minutes, after which a solution of 50 mg (0.11 mmol) rac-N-(5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (example 51) in 0.8 ml dichloromethane was added over a period of 15 minutes. After 30 min stirring, 77 ul (0.55 mmol) triethylamine was added. The reaction mixture was stirred for 15 minutes, then allowed to warm to room temperature and quenched with water and the aqueous layer was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 15%) to provide 44 mg (89%) of the title compound as a white foam. MS (m/e): 453.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9](Br)[CH3:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH:16]([C:18](=[S:22])[O:19]CC)[NH2:17]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:10])[S:22][C:18](=[O:19])[NH:16][N:17]=2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=S)NN
Reactant: CC(Br)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Solvent: CCO
Product: CC1SC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 23 %

Procedure:
22 g (75 mM) of 1-(4-chloro-3-nitrophenyl)-2-bromopropan-1-one and 8 ml (75 mM) of O-ethyl hydrazinecarbothioate in 150 ml of ethanol are refluxed for 16 hours with stirring. The reaction medium is then concentrated under vacuum and the residue obtained is taken up in water. The aqueous phase is extracted twice with ethyl acetate and the combined organic phases are washed with water and then dried over anhydrous sodium sulfate. The solvent is evaporated off under vacuum to give an oil, which is purified on a column of silica using a dichloromethane/acetone mixture (95/5) as eluent. 5 g of 5-(4-chloro-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one are obtained.