Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[CH:12]1([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([OH:23])[C:16]=2[F:24])[CH2:14][CH2:13]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:22]1[C:15]([CH:12]2[CH2:13][CH2:14]2)=[C:16]([F:24])[C:17]([OH:23])=[C:18]([CH:21]=1)[CH:19]=[O:20]
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: O=Cc1ccc(C2CC2)c(F)c1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(C2CC2)c(F)c1O
Reaction time: 3 h
Yield: 134 %

Procedure:
Dibromoisocyanuric acid (1.43 g) was added at room temperature to a DMF (50 mL) solution of 4-cyclopropyl-3-fluoro-2-hydroxybenzaldehyde (1.50 g), and the mixture was stirred at the same temperature as above for 3 hours in a nitrogen atmosphere. A saturated aqueous solution of sodium thiosulfate was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.73 g)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].C[Si](C)(C)Cl.[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>>[S:13]([N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])([CH3:16])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NCCCN1
Agent: C[Si](C)(C)Cl
Product: CS(=O)(=O)N1CCCNC1=O

Procedure:
This compound was produced as described in Example 35 C from 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 49 parts by weight of trimethylchlorosilane and 30 parts by weight of mesylchloride. The reaction product was recrystallized from acetone at low temperature and thereafter from acetone/ethanol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>CO>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[C:12]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: O=Cc1ccccc1
Solvent: C1CCNC1
Solvent: CO
Product: O=c1c(Cc2ccccc2)coc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of the product of Step C (27 g, 91.2 mmole) in 183 mL of methanol was added benzaldehyde (11.1 mL, 109 mmole) followed by pyrrolidine (9.1 mL, 109 mmole). The mixture was stirred at room temperature overnight, cooled to 0° C. and filtered. The solid was washed once with 50 mL of ice-cold methanol and then dried in vacuo; 35.2 g, (75% yield) of the title product was recovered. M.P. 133°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O>CC(O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][O:9]2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Nc1ccccc1CO
Solvent: CC(C)O
Product: Brc1cccc(C2Nc3ccccc3CO2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.5 %

Procedure:
A mixture of 2-amino-benzenemethanol (0.073 mol) and 3-bromo-benzaldehyde (0.073 mol) in 2-propanol (100 mL) was stirred for 3 hours at rt. The solvent was evaporated. Part (3 g) of the residue (20.5 g) was crystallized from hexane. The precipitate was filtered off and dried, yielding 1.37 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[O:14])=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7].[NH3:34]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[C:25]([NH2:34])=[O:26])=[O:14])=[CH:11][CH:10]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: N
Reactant: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(=O)O)cc1
Solvent: c1ccccc1
Product: CCCC/C=C/COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 40 ml of benzene was suspended 2.8 g of (E)-2-[2-[4-(2-heptenyloxy)benzoylamino]phenylthio]benzoic acid followed by addition of 1.2 g of N,N'-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. Ammonia gas was introduced into the mixture with ice-cooling and stirring for 20 minutes and the mixture was then allowed to stand at room temperature for 2 hours. The crystals separated out therefrom were collected by filtration and washed with ethyl acetate to give 2.6 g of the title compound as white crystals.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH+:13]1[C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[N:15]([CH3:22])[CH:14]1[CH3:23].[CH:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:27]=1)=O.CCOCC>C(OC(=O)C)(=O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:22][NH+:15]1[C:16]2=[N:21][CH:20]=[CH:19][N:18]=[C:17]2[N:13]([CH3:12])[CH:14]1[CH:23]=[CH:24][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:27]=1
Reactant: CC1N(C)c2nccnc2[NH+]1C
Reactant: O=Cc1nn(-c2ccccc2)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CN1c2nccnc2[NH+](C)C1C=Cc1nn(-c2ccccc2)c2ccccc12

Procedure:
A mixture of 1,2,3-trimethyl-1H-imidazo[4,5-b]-pyrazinium p-toluenesulfonate (1.67 g, 0.050 mole) and 3-formyl-1-phenylindazole (1.11 g, 0.050 mole) is heated together in acetic anhydride (15 ml) at reflux for 30 minutes. After chilling, ether (500 ml) is added and the solid which separates is filtered off and dried. Yield 1.92 g, (72%). After recrystallization from water the yield of dye is 0.55 g (41%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:41][N:42]([CH:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:43](=[O:58])[CH:44]([NH:56][CH3:57])[CH2:45][C:46]1[CH:55]=[CH:54][C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16](=[O:18])[N:56]([CH3:57])[C@@H:44]([C:43](=[O:58])[N:42]([CH3:41])[C@@H:59]([C:67](=[O:70])[NH:68][CH3:69])[CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:45][C:46]2[CH:55]=[CH:54][C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:47]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.9 %

Procedure:
A solution of 4-(carboxymethoxy)piperidine-1-carboxylic acid tert-butyl ester (228 mg, 0.88 mmol), 1-hydroxy-7-azabenzotriazole (120 mg, 0.88 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg, 0.97 mmol) was stirred for 30 min at room temperature. N-Methyl-2-methylamino-N-(1-methylcarbamoyl-2-phenylethyl)-3-(naphthalen-2-yl)propionamide (355 mg, 0.88 mmol) in 5 ml of dichloromethane was added followed by diisopropylethylamine (0.2 ml, 1.14 mmol) and the mixture was stirred for 2 days at room temperature. The mixture was washed with water (5 ml) aqueous sodium bicarbonate (5 ml), water (2×5 ml), brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (30 g) with ethyl acetate as eluent to give 391 mg of 4-([N-methyl-N-{(1R)-1-(N-methyl-N-[(1R)-1-(methyl carbamoyl)-2-phenylethyl]carbamoyl)-2-(2-naphthyl)ethyl}carbamoyl]methoxy]piperidin-1-carboxylic acid tert-butylester. The product was taken up in 50% trifluoromethane/dichloromethane and allowed to stand for 10 min. Then saturated sodium bicarbonate was added until pH was about 8 and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2×10 ml) and the combined organic phases were washed with brine (5 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (15 g) with dichloromethane:methanol (9:1) to give 327 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14])[C:6]([CH3:12])=[N:7]2.[CH3:27][O-:28].[Na+]>CO>[CH3:27][O:28][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14])[C:6]([CH3:12])=[N:7]2
Reactant: C[O-]
Reactant: Cc1nc2nccc(Cl)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2nc(C)c(C(=O)NCc3cccc(C(F)(F)F)c3)cc12
Yield: 78.9 %

Procedure:
5-Chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide (100 mg, 0.26 mmol) was dissolved in MeOH (10 ml) together with sodium methoxide (30 mg, 0.55 mmol) and refluxed for 18 hours. The reaction was cooled and evaporated, the residue was purified by flash chromatography using CH2Cl2/CH3OH (20:1→10:1) as eluent to give 77 mg (79%) of 5-methoxy-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide as a pale mass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[C:31]([OH:38])[C:30]=1[CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.[CH3:49]O>>[CH3:1][O:2][C:3](=[O:48])[CH2:4][CH2:5][C:6]1[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]3[C:35](=[O:37])[CH:36]=[CH:49][O:38][C:31]=3[C:30]=2[CH2:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc(C(C)=O)c(O)c2CCCc2ccccc2)c1CCC(=O)OC
Reactant: CO
Product: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(=O)ccoc3c2CCCc2ccccc2)c1CCC(=O)OC
Yield: 57.4 %

Procedure:
Using the procedure of example 1 with the modification that methanol was used in place of ethanol, 2-[6-[4-acetyl-3-hydroxy-2-(3-phenylpropyl)phenoxy]hexyl]-6-[(6-methoxy-6-oxohexyl)oxy]benzenepropanoic acid methyl ester from the preceding example was converted into the title compound, a pale-yellow oil purified by flash-chromatography on silica gel (eluting with 3:1 toluene-ethyl acetate), in 57.4% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][N:28]3[CH3:31])=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][N:42]([C:45](=[O:47])[CH3:46])[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.C[Si](Cl)(C)C>C(O)CCC>[CH3:31][N:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][NH:8][C:6]=4[N:7]=[C:2]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([N:39]5[CH2:40][CH2:41][N:42]([C:45](=[O:47])[CH3:46])[CH2:43][CH2:44]5)=[CH:37][CH:38]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cnn(C)c5c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cnn(C)c5c4)c4cc[nH]c4n3)cc2)CC1
Yield: 26.1 %

Procedure:
A mixture of 2-chloro-N-(1-methyl-1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (108 mg, 0.239 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (78 mg, 0.356 mmol) and TMSCl (0.100 mL, 0.791 mmol) in nBuOH (2 mL) was stirred at 135° C. for 20 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give 1-(4-(4-(4-(1-methyl-1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (30 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:23](=[O:24])[CH:22]=[C:21](OC)[C:20](=[O:27])[C:18]=2[N:19]=1>C(O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:23](=[O:24])[CH:22]=[C:21]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:20](=[O:27])[C:18]=2[N:19]=1
Reactant: CN(C)CCN
Reactant: COC1=CC(=O)c2sc(-c3c(F)cccc3F)nc2C1=O
Solvent: CCO
Product: CN(C)CCNC1=CC(=O)c2sc(-c3c(F)cccc3F)nc2C1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
104 ml (0.95 mmol; 1.5 equivalents) of N,N-dimethylethylenediamine are added to 195 mg of 2-(2,6-difluorophenyl)-5-methoxy-1,3-benzothiazole-4,7-dione in solution in 20 ml of anhydrous ethanol. The reaction mixture is stirred at 70° C. for 2 hours then the solvent is evaporated off under reduced pressure. The residue is purified on a silica column (eluent: 5% methanol in dichloromethane). 130 mg (yield=57%) of expected compound is obtained in the form of a red powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Oc1ccc2c(c1)OCCO2
Temperature: 20 °C
Yield: 95 %

Procedure:
A 2000 L reactor was charged with dichloromethane (1303.4 kg) followed by 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (98.0 kg, 597 mol) and stirred until a homogeneous solution was obtained. 3-Chloroperoxybenzoic acid (144.3 kg, 836 mol) was added. The mixture was heated to reflux at a rate of 8-10° C./h, heated at reflux for a further 6 h and allowed to cool to 20° C. The resultant suspension was filtered through a 500 L Nutsche filter and the filter cake was washed with dichloromethane (391 kg). The filtrate and wash solution were transferred to a 2000 L reactor. A 7% by weight aqueous solution of sodium bicarbonate (212.7 kg) was added and the mixture was stirred for 0.5 h. The stirring was stopped and the phases were allowed to separate over 0.5 h. The aqueous layer was removed. The aqueous sodium bicarbonate washing procedure was repeated three times in total. The organic phase was concentrated to dryness under reduced pressure at a temperature <30° C. Methanol (116.1 kg) was added and the resultant mixture was cooled to 0° C. A 15.5% by weight aqueous solution of sodium hydroxide (234.3 kg) was added at a rate of 30-40 kg/h such that the mixture's temperature was maintained between 0-10° C. The mixture was stirred at this temperature for a further 2.25 h and the pH of the mixture was adjusted to 6-7 by the addition of 4 N hydrochloric acid (266.5 kg) such that the mixture's temperature was maintained between 0-10° C. The mixture was allowed to warm to ambient temperature and was extracted three times in total with methyl tert-butyl ether (145 kg for each extraction) by stirring for 0.5 h, stopping the stirring and allowing the phases to separate for 0.5 h. The combined organic extracts were washed three times in total with a 7% aqueous solution of sodium bicarbonate (212.7 kg for each wash) by stirring for 0.5 h, stopping the stirring, allowing the phases to separate for 0.5 h and removing the aqueous phase. The organic phase was then washed with a 30% by weight aqueous solution of sodium chloride (212.7 kg) by stirring for 0.5 h, stopping the stirring, allowing the phases to separate for 0.5 h and removing the aqueous phase. The organic phase was concentrated to dryness under reduced pressure at a temperature <45° C. Tetrahydrofuran (170 kg) was added and the resultant solution concentrated to dryness under reduced pressure at a temperature <45° C. Further tetrahydrofuran (17.1 kg) was added and the resultant solution concentrated to dryness under reduced pressure at a temperature <45° C. Tetrahydrofuran (122.5 kg) was added to afford a brown-red solution of 2,3-dihydro-1,4-benzodioxin-6-ol (86.3 kg, 95%) in tetrahydrofuran which was carried forward without further purification: purity (HPLC-UV at 220 nm) 95.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[N:5]=[C:6]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[CH2:20]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH:8][C:6]2[N:5]=[C:4]([CH3:19])[CH:3]=[C:2]([CH3:1])[N:7]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NCc3ccccc3)cc2)n1

Procedure:
100 mg (0.36 mmol) sulfamethazine and 70.8 μl (0.60 mmol) benzyl bromide were dissolved in 4 ml methanol. Caesium carbonate (113.4 mg, 0.35 mmol) was added and solution was refluxed overnight with stirring. The reaction mixture was then evaporated to dryness, and purified on silica using gradient elution (chloroform to 2% methanol in chloroform) to obtain white crystals in a yield similar to that described in example 1 for step III. 1H NMR (CDCl3, 500 MHz): 7.93 (2H, m), 7.31 (5H, m), 6.58 (3H, m), 4.36 (2H, s), 2.34 (6H, s); MS (ESI+): m/z 369 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41](O)[CH2:42][CH3:43])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1.CCOC(C)=O>[CH2:25]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([CH:41]([O:23][C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:11]([CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH:10]=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH3:24])[N:7]=2)[N:18]=4)[CH2:42][CH3:43])[CH2:37][CH2:36]1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(O)cc2OCC3)n(C(C)C)n1
Reactant: CCC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.1 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol (300 mg, 0.92 mmol), 4-(1-hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (308 mg, 1.11 mmol) and triphenylphosphine (411 mg, 1.38 mmol) in dioxane (5 mL) was added dropwise DEAD (217 ul, 1.38 mmol) and the reaction mixture was stirred at RT for 4 h. The mixture was then diluted with EtOAc and washed with NaOH aq. (1N). The organic phase was washed with brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc) affording 4-{1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]propyl}piperidine-1-carboxylic acid benzylester (280 mg, 51%). 1H NMR (CDCl3, 400 MHz): δ 8.40 (1H, d, J=8.97 Hz), 7.59 (1H, s), 7.37-7.28 (5H, m), 6.73 (1H, dd, J=8.99, 2.56 Hz), 6.54 (1H, d, J=2.52 Hz), 5.98-5.87 (1H, m), 5.14 (2H, s), 4.51-4.45 (2H, m), 4.44-4.37 (2H, m), 4.34-4.19 (2H, bs), 4.09-4.03 (1H, m), 2.83-2.68 (2H, m), 2.43 (3H, s), 1.88-1.78 (1H, m), 1.75-1.61 (5H, m), 1.58 (6H, d, J=6.65 Hz), 1.38-1.30 (1H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:16][C:17]([CH:19]1[CH2:21][CH:20]1[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[C:26]([OH:30])=[C:25]([F:31])[CH:24]=1)=[O:18])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:30][C:26]3[C:25]([F:31])=[CH:24][C:23]([CH2:22][CH:20]4[CH2:21][CH:19]4[C:17]([OH:18])=[O:16])=[CH:28][C:27]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Reactant: ClCc1cccc(SC2CCC2)n1
Product: O=C(O)C1CC1Cc1cc(F)c(OCc2cccc(SC3CCC3)n2)c(F)c1
Yield: 64.1 %

Procedure:
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.021 g, 0.10 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.024 g, 0.10 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 66%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:18]#[N:19].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:18]#[N:19])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cn1
Reaction time: 0.42 h
Yield: 86.6 %

Procedure:
To a solution of 5-benzyloxy-2-chloromethyl-pyridine (2.13 g, 9.11 mmol) described in Manufacturing Example 127-1-3 in ethanol (30 mL) and water (10 mL) was added sodium cyanide (580 mg, 11.8 mmol), which was stirred for 4 hours and 25 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=1:1) to obtain the title compound (1.77 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:25])[C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]=2[CH:24]=1.[ClH:26]>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([F:25])[C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[C:6]=2[CH:24]=1.[ClH:26]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3c(F)cc(Cl)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2c(F)cc(Cl)cc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl 4-(6-chloro-4-fluoro-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D8) (0.203 mmol, 75 mg) and HCl (233 microliters of a 4M solution in 1,4-dioxane) were mixed together and stirred at room temperature for two hours. Solvent was evaporated to afford the title compound, mono hydrochloride salt, complete conversion, M++H=270.