Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:23]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[Cl:32][C:30]1[CH:31]=[C:26]([S:23]([N:18]2[C:19]3[C:15](=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:25])=[O:24])[CH:27]=[C:28]([Cl:33])[CH:29]=1
Reactant: O=S(=O)(c1cc(Cl)cc(Cl)c1)n1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)n1ccc2c(N3CCNCC3)cccc21

Procedure:
A solution of 0.1 g (0.2 mmole) 4-(4-benzyl-piperazin-1-yl)-1-(3,5-dichloro-benzenesulfonyl)-1H-indole and 0.05 mL (0.46 mmole) 1-chloroethyl chloroformate in 10 mL 1,2-dichloroethane was heated under reflux for 0.5 hour. The solution was concentrated under reduced pressure and the residue was dissolved in 6 mL methanol. The solution was heated under reflux for 1 hour, then it was concentrated. 1-(3,5-Dichloro-benzenesulfonyl)-4-piperazin-1-yl-1H-indole (2) was isolated as the hydrochloride salt from methanol/ethyl ether, 74 mg, M+H=410, m.p. 156-157° C.
Reaction SMILES: C[C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH2:13][C:14]([O-:16])=[O:15])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:18][O-].[Na+].Cl>CN(C=O)C.O>[OH:17][C:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[NH:9][C:13]=1[C:14]([O:16][CH3:18])=[O:15]
Reactant: Cc1cccc2c1C(=O)N(CC(=O)[O-])S2(=O)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, a solution of 30 grams (0.117 moles) of methyl-2,3-dihydro-3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide in 50 ml DMF is added, with stirring, to a suspension of 18.9 grams (0.351 moles) of sodium methoxide in 100 ml DMF over a period of about 5 minutes and the internal temperature is maintained at 15°-30°C. by means of an ice bath. The stirring acidification continued for 30 minutes at about 30°C. after the completion of the addition. With external cooling, a solution of 35 ml concentrated HCl in 600 ml of water is added, maintaining the internal temperature below 35°C. After this addition, the mixture is cooled to 10°C. and filtered. The filter cake is washed thoroughly with water and the product is dried. Yield is 23.5 grams (78.2%) m.p. 173°-175°C. The total addition and stirring time prior to acidification should be less than 1 hour. For example, if the addition should take 30 minutes the batch should be stirred only an additional 15-20 minutes.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C=O)C>[ClH:2].[ClH:1].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Reactant: C1COCCN1
Agent: Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCN4CCOCC4)cc23)c1
Yield: 50.9 %

Procedure:
The title product from Example 30 (107 mg, 0.245 mmol) in DMF (2 mL) was treated with morpholine (214 μL, 2.45 mmol) at 80° C. for 24 hours. The reaction mixture was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product (168 mg) was chromatographed on silica using 7.5% methanol/CH2Cl2 to provide 65 mg of pure title product as its free base. This white solid was dissolved in a minimum volume of CHCl3, and titrated with 2 equivalents of 1M HCl in ether to precipitate the title product as a white solid (88 mg; 59%; M.P. 115°-130° C. (dec); LC-MS: 449 (MH+); anal. RP18-HPLC RT: 4.00 min.).
Reaction SMILES: C(O)[C:2]([NH2:7])([CH2:5][OH:6])[CH2:3]O.Cl.CC1[C:16]([OH:17])=[C:15](C=O)[C:14](COP(O)(O)=O)=CN=1.C1C=CC(CNC(CCNNC(C2C=CN=CC=2)=O)=O)=CC=1.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C1C([C@@H](O)[C@H](N)C(O)=O)=CC(O)=C(O)C=1.O=C([C@H](CC1C=C(O)C(O)=CC=1)N)O.CNCC(C1C=CC(O)=C(O)C=1)O.C1C([C@@H](O)CN)=CC(O)=C(O)C=1.C(O)(C(O)=O)C(O)C(O)=O.NCCC1C=CC(O)=C(O)C=1>>[C:16]1([CH:15]=[CH:14][CH:3]=[C:2]([NH2:7])[C:5]=1[OH:6])[OH:17]
Reactant: NC(CO)(CO)CO
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: CNCC(O)c1ccc(O)c(O)c1
Agent: Cl
Agent: NCCc1ccc(O)c(O)c1
Product: Nc1cccc(O)c1O
Reaction time: 0.5 h

Procedure:
The whole brains of mice of ddY-strain were homogenized and the resulting brain homogenate was diluted with the same volume of a buffere solution (comprising 50 mM Tris-HCl (pH 8.6, 1.5 mM EDTA.2Na); 0.5 mM Pridoxal-5-Phosphate; 1 mM Nialamide; and 0.85 mM L-ascorbic acid), and the mixture was centrifuged at 10,000 g to give a supernatant liquid containing the brain enzymes. To this supernatant liquid (500 μl) was added a solution containing 4.5 mM of a substrate selected from L-threo-adrenalinecarboxylic acid, L-threo-DOPS and L-DOPA. The mixture obtained (pH ca. 8, 1.0 ml) was incubated for 30 minutes at 37° C., followed by quantitative determination of adrenaline, noradrenaline or dopamine formed as the reaction product catecholamine.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][Br:17])=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OCC2(C)CCCCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(COc2ccc(CBr)cc2)CCCCC1
Temperature: 25 °C

Procedure:
A solution of 2.2 g (10 mmol) of 4-[((1-methyl)cyclohexyl)methoxy]toluene, 1.8 g (10 mmol) of N-bromosuccinimide and 0.02 g of benzoyl peroxide in 60 ml of carbon tetrachloride was refluxed for 16 hours. The reaction was cooled to room temperature, filtered and the filtrate evaporated to give the product which was used without further purification.
Reaction SMILES: O=[C:2]([C:6]1([C:9]([F:12])([F:11])[F:10])[CH2:8][CH2:7]1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO.O>[C:16]1([N:22]2[C:4]([NH2:5])=[CH:3][C:2]([C:6]3([C:9]([F:10])([F:11])[F:12])[CH2:8][CH2:7]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCC(=O)C1(C(F)(F)F)CC1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(C2(C(F)(F)F)CC2)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.1 %

Procedure:
To 3-oxo-3-(1-(trifluoromethyl)cyclopropyl) propanenitrile (230 mg, 1.3 mmol) in EtOH (5 mL, 200 proof) was added H2O (3.7 mL), 1N NaOH(aq) (1.3 mL), and phenylhydrazine hydrochloride (188 mg, 1.3 mmol) and the mixture heated at 90° C. overnight. After cooling to room temperature, the mixture was diluted with H2O, extracted with EtOAc, the org layer concentrated in vacuo, and purified by column chromatography (5-25% EtOAc/hexanes) to give 1-phenyl-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazol-5-amine (150 mg, 0.56 mmol, 43%). LC-MS (ESI) m/z 268 (M+H)+.
Reaction SMILES: [CH2:1]([OH:10])[C@@H:2]([C@H:4]([C@@H:6]([CH2:8][OH:9])[OH:7])[OH:5])[OH:3].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH2:8]([OH:9])[C@@H:6]([OH:7])[CH:4]([OH:5])[C@H:2]([OH:3])[CH2:1][OH:10]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)C(O)[C@H](O)CO

Procedure:
As can be seen from the results in Table 6, when the production of xylitol was performed through fed-batch culture using the new mutant strain, xylitol was produced for 72 hours was produced in a concentration of 201.3 g/L for 72 hours, suggesting a xylitol yield of 97% and a xylitol productivity of 2.80 g/L/h. Glucose contained in the corncob hydrolyzate was completely consumed during the cell culture process, and 23.7 g/L corresponding to 85% of the total amount (27.9 g/l) of arabinose added remained as arabinose, and 4.2 g/L corresponding to 15% was converted to arabitol. Herein, the concentration of final xylitol concentration (201.3 g/L) to arabitol concentration (4.2 g/L) was 100:2.1, resulting from a decrease arabitol production of 65% compared to the parent strain.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([N:14]1[CH2:24][CH2:23][C:17]2[N:18]=[N:19][C:20]([SH:22])=[CH:21][C:16]=2[CH2:15]1)=[O:13])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:9]([O:11][C:12]([N:14]1[CH2:24][CH2:23][C:17]2[N:18]=[N:19][C:20]([S:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:16]=2[CH2:15]1)=[O:13])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2nnc(SCc3ccccc3)cc2C1
Reaction time: 20 h

Procedure:
A mixture of 13.2 g of benzyl bromide in 75 cc of dimethyl formamide is added dropwise within 2 hours to a suspension heated to 50° of 18.5 g of 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and 12.8 g of potassium carbonate in 200 cc of dimethyl formamide. The mixture is subsequently stirred at the same temperature for 20 hours and is then completely concentrated in a vacuum. The residue is divided between 200 cc of chloroform and 50 cc of water, the organic phase is separated and concentrated to a dark oil in a vacuum. This is chromatographed on an aluminum oxide column, and elution is effected with a mixture of benzene/petroleum ether 2:1. The crude oily 3-benzylmercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, obtained after concentrating the eluate, crystallizes from 75 cc of ether after the addition of 25 cc of petroleum ether.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[C:14]([CH:19]=O)=[N:15][CH:16]=[CH:17][CH:18]=1>O.C(O)C>[OH:12][C:13]1[C:14]([CH:19]=[N:10][NH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ncccc1O
Reactant: NNC(=O)Nc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1ncccc1O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
4-Phenyl semicarbazide (4.91 g, 33 mmol) was added to a suspension of 3-hydroxy-2-pyridine carbaldehyde (4.0 g, 33 mmol) in a mixture of ethanol water (30 mL:40 mL). The reaction mixture was stirred at room temperature for 3 h and the yellow product was collected by filtration. The yellow precipitate was washed with EtOH/H2O 1:1 and dried under P2 O5 to yield 8.22 g (99%) of product. It can be recrystallized from EtOH/H2O; m.p. 201°-2° C. (dec.). 1H NMR (d6 -DMSO) d: 10.85 (br.s., 1H); 10.6 (br.s., 1H); 9.14 (s, 1H); 8.27 (s, 1H); 8.15 (d 9f d, 1H); 7.55 (d, 2H); 7.26-7.36 (m, 4H); 7.01 (t, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:26]=[CH:25][CH:24]=[CH:23][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH2:10][C@H:9]2[CH3:22])=[N:6][N:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:22][C@H:9]1[N:8]([C:5]2[C:4]3[CH:23]=[CH:24][CH:25]=[N:26][C:3]=3[C:2]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:7][N:6]=2)[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[CH2:10]1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2ncccc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(-c2ccccc2)c2ncccc12
Yield: 76.6 %

Procedure:
Using methods described in Example 6, and starting with (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 80 (68 mg, 185 μmol), tetrakis(triphenylphosphine)palladium (11 mg, 9 μmol), phenylboronic acid (34 mg, 277 μmol), and 2 M sodium carbonate (185 μl, 370 μmol) yielded (R)-(3-methyl-4-(8-phenylpyrido[3,2-d]pyridazin-5-yl)piperazin-1-yl)(phenyl)methanone 81 (58 mg, 77% yield) after chromatographic purification. MS 409.2 (calc'd) 410.2 (M+H, found).
Reaction SMILES: [ClH:1].[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[C:25]([NH:36][CH:37]5[CH2:43][CH:42]6[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]6)[CH2:38]5)[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]>O1CCOCC1>[ClH:1].[C:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([C:23]4[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:36][CH:37]5[CH2:43][CH:42]6[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]6)[CH2:38]5)[CH:24]=4)[C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:3]
Reactant: CN1C2CCC1CC(Nc1cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc1C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: C1COCCO1
Product: CN1C2CCC1CC(Nc1cc(-n3c4ccccc4c4c(-c5ccc(C#N)nc5)cccc43)ccc1C(=O)O)C2
Temperature: 100 °C

Procedure:
3.49 ml of 1N hydrochloric acid are added to a solution of 340 mg of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzoate in 6 ml of dioxane. The reaction mixture is heated at 100° C. in a microwave for 2 hours and then concentrated under reduced pressure. The residue is purified by trituration with diisopropyl ether, so as to give 330 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)amino]benzoic acid hydrochloride in the form of a pale yellow powder, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][C:49]([S:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])=[CH:48][CH:47]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOCCSc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOCCSc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (310 mg) was added toluene/ethanol/water (10/1/1, 19.8 ml) and then were added 4-(2-propoxyethylthio)phenyl borate (172 mg) and potassium carbonate (181 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (28 mg), and the mixture was refluxed at 100° C. for 12 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and. recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[4-(2-propoxyethylthio)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 105) (220 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][C:10]([CH:12]1C(=O)OC(C)(C)[O:14][C:13]1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O>[O:14]=[C:13]1[CH2:12][C:10](=[O:11])[CH2:9][CH2:8][N:7]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)CC1=O

Procedure:
A solution of tert-butyl[3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-oxopropyl]carbamate (8.3 g, 26.3 mmol) in EtOAc (130 mL) was heated at reflux for 4 h. The solution was concentrated to afford the title compound which was used without further purification. LRMS (ESI) m/z 214.2 [(M+H)+; calcd for C10H15NO4: 214].
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([S@:12]([CH2:14][CH2:15][CH3:16])=[O:13])[N:9]=[C:8]([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])[CH:7]=1>C1COCC1>[CH:18]([NH:17][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S@:12]([CH2:14][CH2:15][CH3:16])=[O:13])[N:9]=1)[C:5]([OH:22])=[O:4])([CH2:20][CH3:21])[CH3:19]
Reactant: CCC[S@](=O)c1cc(C(=O)OC)cc(NC(C)CC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC[S@](=O)c1cc(C(=O)O)cc(NC(C)CC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Add 1 N lithium hydroxide (1.15 mL, 1.15 mmol) to a solution of (S)-2-sec-butylamino-6-(propane-1-sulfinyl)-isonicotinic acid methyl ester (0.229 g, 0.767 mmol) in THF (2 mL) at 0° C. Stir at room temperature for 3 h, acidify the solution to about pH=2 and concentrate to one half of the solvent. Partition the residue between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (2×10 mL). Wash the combine organic extract with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (95%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=O.[NH2:13][C:14]([NH2:16])=[S:15]>CO>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])[N:13]=1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: NC(N)=S
Solvent: CO
Product: N#Cc1cccc(-c2csc(N)n2)c1
Temperature: 0 °C

Procedure:
16.9 g of 3-bromoacetyl-benzonitrile were placed in 50 ml of methanol and treated at room temperature with 8 g of thiourea. The mixture was boiled for 2 1/2 hours and then cooled to 0° C. while stirring slowly. The product separated as the salt, was filtered off and converted into the base by the addition of 100 ml of 2N sodium hydroxide solution. The aqueous suspension was extracted with a total of 700 ml of methylene chloride and the organic phase was dried with magnesium sulphate. 9.6 g of 3-(2-amino-thiazol-4-yl)-benzonitrile separated upon concentration.
Reaction SMILES: Cl.[I:2][C:3]1([CH2:6][C@H:7]([CH2:16][O:17][Si](C)(C)C(C)(C)C)[O:8][Si](C)(C)C(C)(C)C)[CH2:5][CH2:4]1>C1COCC1>[I:2][C:3]1([CH2:6][C@@H:7]([OH:8])[CH2:16][OH:17])[CH2:5][CH2:4]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CC1(I)CC1)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: OC[C@H](O)CC1(I)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Aqueous HCl solution (0.3 mL, 1N) was added to a solution of (R)-5-((1-iodocyclopropyl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (step E, 281 mg, 0.598 mmol) in THF (2 mL) at 0° C. The mixture was slowly warmed at room temperature and stirred for 24 hours. The reaction was quenched by addition of aqueous NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to provide (R)-3-(1-iodocyclopropyl)propane-1,2-diol (0.598 mmol), which was used in the next step with no further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C@H:9]([CH2:10][N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])[C@H:8]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]1=[O:28].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[O:28]=[C:7]1[C@@H:8]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:9]([CH2:10][N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2CCOC2=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CN1CCOC1=O)OCc1ccccc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidin-3-yl)carbamate (3.84 g, 8.18 mmol), K2S2O8 (3.10 g, 11.5 mmol) and K2HPO4 (1.852 g, 10.6 mmol) in ACN:water (2:1, 136 mL) while heating for 40 min at 90° C. More K2S2O8 (663 g, 2.45 mmol) and K2HPO4 (370 mg, 2.13 mmol) were added and it was heated for another 3 h. More K2S2O8 (332 mg, 1.23 mmol) and K2HPO4 (185 mg, 1.06 mmol) were added, and it was heated for an additional 2 h, whereupon it was concentrated in vacuo, removing most of the ACN. The mixture was diluted with brine/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-100% then MeOH-DCM, 10%) to afford the title compound (1.61 g, 62%) as a beige foam. LCMS: Rt=0.51 min, m/z=320.0 (M+1) Method 2m_acidic.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19]>>[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31](=[O:32])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:17])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:19])[CH3:20]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CN(C)c1ccc(CNc2ccccc2)cc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)N(Cc1ccc(N(C)C)cc1)c1ccccc1

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl]phenylamine (0.70 g) and 2,6-diisopropylphenyl isocyanate (0.74 mL) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-phenylurea (0.46 g) was obtained.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[OH:3].[ClH:6].[CH2:7]([O:9]CC)[CH3:8]>C(O)C>[ClH:6].[CH2:7]([O:9][C:1](=[NH:5])[CH:2]([OH:3])[CH3:4])[CH3:8]
Reactant: CC(O)C#N
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)C(C)O
Reaction time: 60 h

Procedure:
A solution of lactonitrile (378 g, 5.32 mol) in ethyl ether (1.46 L) and ethanol (0.34 L) was saturated with hydrogen chloride gas at 0-5° C. for 0.5 h and kept at 5° C. for 60 h. The resulting precipitate was filtered off and washed twice with ethyl ether to give the title compound of Preparation Twelve, Step A as a solid, 815 g (99%). mp: 165-168° C.; 1H NMR (CD3OD, 250 MHz) δ 1.45-1.53 (c, 6H), 4.40-4.61 (c, 3H).