Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:41]([CH3:42])=[CH:40][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH:19]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([CH3:39])[N:34]=[CH:33]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2N=C(N3CCN(C)C(C4C=C5C(=CC=4)N(C)N=C5)C3)SC=2C=1C1C=CC(Cl)=CC=1)C(OCC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:41]([CH3:42])=[CH:40][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([CH3:39])[N:34]=[CH:33]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:43]1[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Product: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid (12 mg) was prepared in a similar manner as compound (2S)-2-tert-butoxy-2-(2-(4-(tert-butoxycarbonyl)-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate instead of tert-butyl 4-(6-((S)-1-tert-butoxy-2-ethoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-2-(1-methyl-1H-indazol-5-yl)piperazine-1-carboxylate. LCMS-ESI+: calc'd for C33H37ClN5O3S: 618.2 (M+H+); Found: 618.4 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 8.11 (m, 1H), 7.98 (m, 1H), 7.77 (m, 1H), 7.60 (m, 1H), 7.55-7.46 (m, 4H), 7.38 (s, 1H), 5.15 (s, 1H), 4.40 (m, 2H), 4.35 (m, 1H), 4.11 (s, 3H), 3.9-3.7 (m, 3H), 3.45 (m, 1H), 2.68 (s, 3H), 2.50 (s, 3H), 0.94 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:23][C:24]=1F>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][C:24]3[CH:23]=[CH:22][C:21]([C:26]([F:29])([F:28])[F:27])=[CH:20][C:19]=3[Cl:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: Oc1ccc2c(ccn2Cc2ccccc2)c1
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(Oc2ccc3c(ccn3Cc3ccccc3)c2)c(Cl)c1
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A slurry of 0.413 g (1.85 mmol) 1-benzyl-5-hydroxy-1H-indole, 0.3 ml (2.2 mmol) 3-chloro-4-fluorobenzotrifluoride, and 1.0 g (3.0 mmol) Cs2Cb3 in 12 ml DMF was heated to 130° C. with stirring for 16 hr. The solution was allowed to cool and then filtered to remove Cs2CO3. The solution was concentrated under vacuum and chromatographed on silica using 5-7% EtOAc-hexane to afford 0.51 g 1-benzyl-5-(2-chloro-4-trifluoromethyl-phenoxy)-1H-indole as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[C:22](=[O:23])[NH:21][N:20]=[N:19]3)[CH:13]=2)[C:10](=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26]>CC(O)=O>[O:24]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2](/[CH:1]=[CH:31]/[C:30]2[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)[N:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]2[C:22](=[O:23])[NH:21][N:20]=[N:19]2)[CH:13]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1cccc(-n2nn[nH]c2=O)c1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(/C=C/c2nc3ccccc3c(=O)n2-c2cccc(-n3nn[nH]c3=O)c2)cc1
Reaction time: 72 h
Yield: 70 %

Procedure:
A mixture of 2-methyl-3-(3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)phenyl)quinazolin-4(3H)-one (32 mg, 0.1 mmol) and 4-cyanobenzaldehyde (16 mg, 0.12 mmol) in AcOH (5 mL) was heated to reflux and stirred for 3 days (continuously monitored by LC/MS, which indicated product formation after 3 hr). After cooling, the mixture was dry-loaded onto silica gel and purified by column chromatography on silica gel using CH2Cl2/MeOH (1:0 to 95:5) as eluent to give a solid (11 mg; desired product ca. 70% purity). The solid was re-purified by preparative thin-layer chromatography using CH2Cl2/MeOH (9:1) as eluent to give the product (6 mg, 14%) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][Br:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: BrCCCCCBr
Solvent: Cc1ccccc1
Product: BrCCCCCOc1ccc(OCc2ccccc2)cc1
Reaction time: 120 h

Procedure:
4-Benzyloxyphenol and 1,5-dibromopentane were reacted under conditions described in Example 15 for 5 days. The crude product isolated by a toluene extraction, was distilled to give 1-benzyloxy-4-(5-bromopentoxy)benzene as an oil (88.9% pure by gas chromatography).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3][C:4]1[CH:5]=[C:6]([N:10]=[C:11]=S)[CH:7]=[CH:8][CH:9]=1.[OH:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH3:35])=[C:30]([NH2:36])[CH:29]=2)[CH:24]=[CH:23][N:22]=1)=[O:20]>CO>[OH:15][CH2:16][CH2:17][NH:18][C:19]([C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]3[N:34]([CH3:35])[C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:14])([F:13])[F:1])[CH:5]=4)=[N:36][C:30]=3[CH:29]=2)[CH:24]=[CH:23][N:22]=1)=[O:20]
Reactant: CNc1ccc(Oc2ccnc(C(=O)NCCO)c2)cc1N
Reactant: FC(F)(F)Sc1cccc(N=C=S)c1
Solvent: CO
Product: Cn1c(Nc2cccc(SC(F)(F)F)c2)nc2cc(Oc3ccnc(C(=O)NCCO)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with 3-(trifluoromethylthio)phenylisothiocyanate (1 eq), 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide (1 eq), and MeOH. The reaction was maintained at rt overnight. Ferric chloride, (1.5 eq) was added and the resulting red reaction mixture was stirred overnight. The reaction was partitioned with EtOAc and water, and filtered through Celite. The layers were separated and the aqueous phase was neutralized with saturated Na2CO3 solution. The resulting aqueous phase was extracted with EtOAc and the mixture was filtered through Celite. The phases were separated and the aqueous phase was again extracted and filtered. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated to give a brown solid. The crude residue was purified by reverse phase HPLC. LCMS m/z 504.1 (MH+), tR=3.7 min.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=O>O>[CH3:14][CH2:13][O:12][C:8]([CH:9]1[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)=[O:11]
Reactant: CCOC(=O)C=O
Reactant: N[C@@H](CS)C(=O)O
Solvent: O
Product: CCOC(=O)C1NC(C(=O)O)CS1
Temperature: 25 °C
Reaction time: 50 h
Yield: 29313.2 %

Procedure:
L-Cysteine (60.4 g, 0.50 mmol) and ethyl glyoxylate (polymer, 47% toluene solution, 50.9 g, 0.234 mol) were added to water (150 ml), and the mixture was stirred at room temperature for 50 hours. The obtained solution was concentrated under reduced pressure, and the precipitated solid was collected by filtration. The obtained white solid (about 40 g) was suspended in water (100 ml), and the suspension was stirred for 16 hours at slurry state. The white crystals were collected by filtration, and dried under reduced pressure to give thiazolidine-2,4-dicarboxylic acid 2-ethyl ester as a white solid (30.08 g).
Reaction SMILES: [N:1]1[CH2:2][C:3](=[N:7][CH2:8][CH3:9])[CH:4]=[CH:5][CH:6]=1.C(N)[C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1>>[N:1]1[CH2:2][C:3](=[N:7][CH2:8][C:9]2[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: NCc1ccccc1
Reactant: CCN=C1C=CC=NC1
Product: C1=CC(=NCc2ccccc2)CN=C1
Yield: 98 %

Procedure:
The procedure described for the preparation of compound (XVII) was used, replacing p-methoxybenzylamine with benzylamine, to obtain 3.26 g (98%) of N-(3-pyridylidene)-benzylamine (XXIII).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][OH:24]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:23][OH:24])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Br)cc2F)cc1
Agent: Cl
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Br)cc2F)cc1
Yield: 91 %

Procedure:
In a manner similar to that described for Example 4, Step (c), 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (1.05 g, 0.00300 mol) was allowed to react with hydroxylamine hydrochloride (0.256 g, 0.00368 mol) to give 1.00 g of 4-(4′-bromo-2′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as a white solid; mp 163-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:32].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[C:5]2[CH:10]=[N:9][N:8]([CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:6]=2[N:7]=1
Reactant: CC(Br)c1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3[nH]ncc23)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)c2ccccc2)c(=O)[nH]1
Yield: 82 %

Procedure:
6-Bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.25 g, 0.66 mmol) was dissolved in DMF (3 mL) and K2CO3 (0.17 g, 0.79 mmol) and (1-bromoethyl)benzene (0.148 g, 0.799 mmol) was added to it. The reaction mixture was refluxed for overnight. On completion, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to obtain the desired intermediate (0.26 g, 92.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.CCCCCCC.C(=O)(O)[O-].[K+].[CH2:38]([S:42](Cl)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]>O>[CH2:38]([S:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:8]([O:10][CH3:11])=[O:9])=[CH:24][CH:25]=1)(=[O:44])=[O:43])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCC(Oc1ccc(N)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCCCC
Solvent: O
Product: CCCCCCCCCCCCC(Oc1ccc(NS(=O)(=O)CCCC)cc1)C(=O)OC

Procedure:
A heel was created batchwise by charging 142.2 g (0.41 moles) of methyl 2-[4-aminophenoxy]tetradecanoate (the amine), 267.7 g of heptane, 45.7 g (0.46 moles) of potassium bicarbonate, and 119.7 g of deionized water. The two-phase mixture was stirred with high agitation (800-900 rpm) and heated to 55° C-60° C. at which point 71.4 g of butanesulfonyl chloride was added over approximately 1 hour. After stirring for one hour, the composition of the assay of the product in the upper organic phase was 98.9%. At this point, continuous feeds into the reactor system, which consists of two reactors and a processing tank, were started to provide six hours of residence time in the two reactors. The feed rates were: 1.46 g/min (2.63 mmoles/min) of the amine solution (63 wt % in heptane), 0.45 g/min (2.87 mmoles/min) of the butanesulfonyl chloride, and 1.42 g/min (2.87 mmoles/min) of a 20 wt % potassium bicarbonate solution.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:9](=[O:22])[NH:8]2)[CH:5]=[N:4][CH:3]=[N:2]1.C(O)=O>CO.[Pd]>[N:1]1([CH2:6][C@H:7]2[NH:8][C:9](=[O:22])[C@H:10]2[NH2:11])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reaction time: 1 h

Procedure:
To a solution of benzyl ((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (38 mg, 0.126 mmol) in MeOH (5 mL) was added Pd black (6.7 mg, 0.063 mmol) followed by formic acid (339 μL, 8.83 mmol). After 1 h of stirring, the mixture was filtered over celite, washing with MeOH, and the filtrate was concentrated in vacuo. The solution was lyophilized and the crude material was used directly in the subsequent step. LCMS: Rt=0.14 min, m/z=168.1 (M+1) Method 2m_acidic.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[C:6]=2[N:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[N:3]=[CH:4][C:5]3[N:10]=[N:9][N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[C:6]=3[N:7]=2)[CH:25]=[N:24]1
Reactant: Clc1ncc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2ncc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 80 °C
Yield: 28.6 %

Procedure:
To a solution of 6-((5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl)methyl)quinoline (393 mg, 1.33 mmol) in DME (8 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (415 mg, 1.99 mmol) and Cs2CO3 (1.30 g, 3.98 mmol) in H2O (1.3 mL). The reaction mixture was degassed twice. The palladium catalyst Pd(dppf).CH2Cl2 (63 mg, 0.077 mmol) was added and the reaction mixture was degassed for two more times, and heated to 80° C. for 15 h under nitrogen. After cooling to room temperature, the solvent was removed under reduced pressure. Flash chromatography of the residue over silica gel, using 50% hexane in EtOAc to 100% EtOAc to 10% MeOH in EtOAc, gave the desired product (130 mg, 29%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.00 (s, 3H), 6.04 (s, 2H), 7.39-8.29 (m, 7H), 8.92 (m, 1H), 9.44 (s, 1H); LCMS (APCI) m/z 343.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:12]([O:16][C:17](=[O:26])[NH:18][CH2:19][CH:20]1[CH2:21][CH2:22][N:23]([C:5]2[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:24][CH2:25]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A suspension of 1.00 g (4.21 mmol) 5-bromo-2-chloro-3-nitro-pyridine, 0.993 g (4.63 mmol) of piperidin-4-ylmethyl-carbamic acid tert-butyl ester, and 1.16 g (8.42 mmol) of potassium carbonate in N,N-dimethylformamide (10 mL) is stirred for 2 hours under argon. The mixture is diluted with water which causes a solid to precipitate from solution. The formed solid is collected by filtration, washed with water, and dried for 1 hour under vacuum at 50° C. to give 1.57 g (90.0%) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester as a yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7](=[O:12])[NH:8][S:9](=[O:11])(=[O:10])[C:5]=2[CH:4]=1.[CH3:15][CH:16]([OH:18])[CH3:17]>>[CH3:15][CH:16]([O:18][C:7](=[O:12])[C:6]1[CH:13]=[CH:14][C:3]([Cl:2])=[CH:4][C:5]=1[S:9]([NH2:8])(=[O:11])=[O:10])[CH3:17]
Reactant: CC(C)O
Reactant: O=C1NS(=O)(=O)c2cc(Cl)ccc21
Agent: Cl
Product: CC(C)OC(=O)c1ccc(Cl)cc1S(N)(=O)=O
Temperature: 80 °C

Procedure:
Anhydrous hydrogen chloride was passed into a mixture of 773.7 g of 6-chloro-1,2-benzothiazole-3-one-1,1-dioxide and 7 L of 2-propanol until the mixture was saturated (7.5 hr.). The mixture was heated at reflux (80° C.) for 1.5 hr., then cooled to 0° C. The precipitated solids were collected and dried to give 893.9 g of the title compound, m.p. 143°-145° C. A second crop (44.5 g, m.p. 140°-142° C.) and third crop (125 g, m.p. 133°-135° C.) were obtained by concentrating the mother liquors in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([F:11])[C:9]=1[OH:10]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cc(F)c(O)c(F)c1
Temperature: 110 °C
Yield: 70.8 %

Procedure:
3,5-Difluoro-4-hydroxybenzaldehyde (2.27 g, 14.4 mmol), nitromethane (4.7 mL, 86.4 mmol) and ammonium acetate (4.4 g, 57.6 mmol) were dissolved in acetic acid (22 mL) and the reaction mixture was heated at 110° C. for 1 hour 30 min. The reaction was concentrated under reduced pressure and the residue partitioned between ether and water, the layers were separated and the organic layer was dried with Na2SO4. The organic mixture was filtered and the filtrate concentrated under reduced pressure to afford a crude product. The crude product was purified by flash column chromatography (eluent: EtOAc/hexane 22/78) to afford the title compound (2.05 g, yield: 71%). Electrospray MS M−1 ion=200. 1H-NMR (CDCl3, 200 MHz): 7.84 (d, 1H, J=13.7 Hz), 7.45 (d, 1H, J=13.7 Hz), 7.19-6.99 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: O=C1Cc2cccc(Nc3ccccc3Cl)c2N1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1Nc1ccccc1Cl

Procedure:
A mixture of 2-oxo-7-(2-chloroanilino)indoline (5 g.), sodium hydroxide (1.25 g.), dioxane (30 ml.) and water (60 ml.) was refluxed under heating for 53 hours with stirring. After cooling, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in water (50 ml.), washed with ethyl acetate, adjusted to pH 4 to 5 with 5% sulfuric acid and then extracted with ethyl acetate (150 ml.). The extract was evaporated under reduced pressure and the residue was subjected to column chromatography on silica gel (60 g.) and eluted with ethyl acetate to give 2-[2-amino-3-(2-chloroanilino)phenyl]acetic acid (2.4 g.). mp 230° to 232° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1CCCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: [H][H]
Solvent: C1CCCCC1
Product: CC(C)(C)C1CCC(O)CC1
Reaction time: 2.25 h
Yield: 98 %

Procedure:
A mixture consisting of 50 g (0.33 mole) of 4-tert-butyl-phenol, 1.35 g of the catalyst prepared as described above under example 1A and 100 g of cyclohexane was introduced in an autoclave under nitrogen and then hydrogen was introduced until a stable pressure around 16×105Pa had been established. The reaction mixture was then heated to about 98° and the reaction was followed by gas chromatography. After 135 min, the reaction was interrupted by cooling to around 45° and the autoclave was purged with a nitrogen flow. After filtering, the catalyst was recovered under a flow of argon, washed with cyclohexane and recycled for the following hydrogenation operations. 4-tert-Butyl-cyclohexanol was obtained by distillation of the clear filtrate in 98% yield. The isomeric content was 81.9% of the cis isomer and 15.9% of the trans isomer.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[CH:11]=[C:10]([F:18])[C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22](OC)=[O:23])=[CH:8][C:7]2=1)(=[O:3])[NH2:2].Cl.[NH:29]1[CH2:32][CH:31]([C:33]#[N:34])[CH2:30]1.C(N(CC)CC)C>CO>[C:33]([CH:31]1[CH2:32][N:29]([C:22](=[O:23])[C:21]([OH:27])([CH3:26])[C:20]#[C:19][C:9]2[C:10]([F:18])=[CH:11][C:12]3[O:13][CH2:14][CH2:15][N:16]4[C:6](=[N:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:17]4)[C:7]=3[CH:8]=2)[CH2:30]1)#[N:34]
Reactant: N#CC1CNC1
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)N1CC(C#N)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
Into a 10-mL sealed tube, was placed a solution of methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(10),2,4,11,13-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (150 mg, 0.40 mmol, 1.00 equiv), azetidine-3-carbonitrile hydrochloride (237 mg, 2.00 mmol, 5.00 equiv), triethylamine (203 mg, 2.01 mmol, 5.00 equiv) in methanol (5 mL). The resulting solution was stirred for 12 h at 40° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1). This resulted in 8.8 mg (5%) of 9-[4-(3-Cyano-azetidin-1-yl)-3-hydroxy-3-methyl-4-oxo-but-1-ynyl]-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a off-white solid. LC-MS: (ES, m/z): 424 [M+H]+1H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.594 (d, 1H), 7.785 (s, 1H), 7.562 (d, 1H), 7.145 (s, 1H), 7.062 (d, 1H), 6.438 (d, 1H), 4.748 (t, 1H), 4.600-4.410 (m, 5H), 4.300-4.190 (m, 1H), 4.180-4.000 (m, 1H), 3.900-3.710 (m, 1H), 1.610 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.Cl.[CH3:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:15][N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)[CH3:17]
Reactant: CNC
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NCc1ccc(CN(C)C)cc1
Yield: 136.1 %

Procedure:
N-(4-Chloromethylphenylmethyl)acetamide (20.0 g) and dimethylamine hydrochloride (9.1 g) were dissolved in acetonitrile (190 ml), and potassium carbonate (28 g) was added. The mixture was refluxed under heating overnight. An insoluble solid was filtered off and the solvent was evaporated to give the objective N-(4-dimethylaminomethylphenylmethyl)acetamide (28.4 g) as an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[C@@H:7]1[CH2:11][C@@H:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][N:8]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[P:33]([O:40]CC)([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:8]2[CH2:9][C@H:10]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][C@H:7]2/[CH:6]=[CH:5]\[CH2:4][CH2:3][CH2:2][P:33]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:40])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CCOP(OCC)OCC
Reactant: O=S(=O)(N[C@@H]1C[C@@H](/C=C\CCCBr)N(S(=O)(=O)c2ccc(Cl)cc2)C1)c1ccc(Cl)cc1
Product: CCOP(=O)(CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1)OCC

Procedure:
A mixture of (2S,4R)-2-[(Z)-5-bromo-1-pentenyl]-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)pyrrolidine (200 mg) and triethyl phosphite (5.0 ml) was refluxed for 3 hours and evaporated in vacuo to give an oil. The oil was chromatographed on silica gel column with chloroform as an eluent to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-diethoxyphosphoryl-1-pentenyl]pyrrolidine (164 mg) as an oil.