Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.C([O-])(=O)C.[Na+].Cl.[Cl:32][CH2:33][CH2:34][NH2:35]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:35][CH2:34][CH2:33][Cl:32])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: NCCCl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCCCl)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 24 h
Yield: 30 %

Procedure:
To a solution of 100 mg mitomycin A (0.286 mmol) in 10 ml. of anhydrous methanol, a solution of 82 mg sodium acetate (1 mmol) in 2.5 ml. of methanol and a solution of 116 mg 2-chloroethylamine hydrochloride (1 mmol) in 2.5 ml. of methanol were added alternatively with constant stirring, over a period of ten minutes. The stirred reaction mixture was periodically checked by TLC and the reaction appeared to be complete in 24 hours. The insoluble sodium chloride was removed by filtration and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography using ethyl acetate and acetone (4:1 by volume) as the eluant. Recrystallization from a mixture of chloroform and hexane gave 34 mg. (30% yield) of the desired product as purple-colored crystals having a melting point of 59° C. (decomposing) and providing the following analysis:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][CH:20]([F:41])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([O:39]C)=O)=[N:29]1>C(Cl)Cl>[F:41][CH:20]([F:19])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([N:3]([O:4][CH3:5])[CH3:2])=[O:39])=[N:29]1
Reactant: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54.0 mmol) and iPr2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added AlMe3 (1.8 M solution in toluene, 30.0 mL, 54.0 mmol) dropwise at 0° C. After stirring at 0° C. for 1 h, a solution of methyl 1-[2-(difluoromethoxy)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5.87 g, 17.99 mmol) in CH2Cl2 (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as pale yellow crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.68 (3H, s), 3.89 (3H, s), 6.52 (1H, t, J=72.6 Hz), 7.37 (2H, m), 7.46-7.53 (1H, m), 7.62 (1H, dd, J=7.8, 1.5 Hz), 7.76 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14](=[O:34])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][CH:16]=3)[C:6]=2[CH:35]=1.[CH3:36][S:37]([Cl:40])(=[O:39])=[O:38]>O1CCCC1>[CH3:13][CH2:12][CH2:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:35][C:6]=2[C:7]=1[C:14]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)=[O:34].[ClH:40]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Product: Cl
Temperature: 12.5 °C

Procedure:
Under a temperature range from room temperature to reflux temperature, preferably reflux temperature, 5-amino-2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)benzofuran is reacted with methanesulfonyl chloride in tetrahydrofuran solvent to provide a crude dronedarone hydrochloride, wherein an amount of tetrahydrofuran used is in the range of 0 to 15 parts by volume, preferably 3 to 12 parts by volume, more preferably 5 to 10 parts by volume based on 1 part by weight of the compound A, and an amount of methanesulfonyl chloride used is in the range of is 1 to 8 equivalents, and preferably 1.5 to 5 equivalents, and more preferably 2 to 3 equivalents relative to the compound A to obtain a reaction mixture. When the reaction is terminated, the reaction mixture is cooled to −25 to 50° C., preferably −15 to 40° C., more preferably −10 to 35° C. to obtain crude dronedarone hydrochloride. Then the crude dronedarone hydrochloride can be purified to obtain highly pure dronedarone hydrochloride. If desired, the obtained dronedarone hydrochloride can be converted to highly pure dronedarone via alkaline solvent, or further converted to other pharmaceutically acceptable salts of dronedarone.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([CH3:12])=[O:32])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2Cl)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2Cl)ccn1
Reaction time: 0.62 h

Procedure:
To the solution of 4-(7-chloro-2-(methylthio)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (64 mg, 0.175 mmol, 1.0 eq) in 5 mL of DCM was added MCPBA (33 mg, 0.192 mmol, 1.1 eq) at 0° C. and reaction stirred for 30-45 min. Thereafter, it was quenched with water (10 mL) and aqueous phase extracted with ethyl acetate (25 mL×5), combined organic layers dried over sodium sulfate, filtered and condensed under reduced pressure to yield crude product which was sufficiently pure and was carried to next step without further purification. LC/MS (m/z) [382.0] (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH3:9].[Br:10]Br>[W]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9][Br:10]
Reactant: Cc1cc(Br)ccc1Br
Reactant: BrBr
Agent: [W]
Product: BrCc1cc(Br)ccc1Br
Reaction time: 0.17 h

Procedure:
33 g (0.1 mole) 2,5-dibromo toluene is placed in a 100 ml three-necked flask, fitted with a reflux condenser, a sealed mechanical stirrer, and a separatory funnel with the stem reaching nearly to the bottom of the flask. The flask is illuminated with two 300-watt tungsten lamps during the reaction. The flask is heated in an oil bath to 150.C, and 18.4 g (5.9 ml, 0.115 mole) bromine is added over two hours. The mixture is stirred for an additional 10 minutes, and the contents, while still liquid, are poured into a 500 ml round-bottom flask containing 300 ml of hot light petroleum ether and 2 g decolorizing carbon. A reflux condenser is attached, and the mixture is heated to reflux until the material dissolves, then rapidly filtered through a pre-heated Buchner funnel. The filtrate is cooled and washed with cold light petroleum.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=1>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=2)=[N:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 79.7 %

Procedure:
Potassium carbonate (1.4 g) and 2-bromo-5-trifluoromethylpyridine (450 mg) were added to an acetonitrile solution (10 mL) of ethyl 4-hydroxybenzenecarboxylate (221 mg), and heated overnight under reflux. The reaction solution was concentrated under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain the entitled compound (330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44]1[CH:56]=[CH:55][C:47](CN2C=CC(N)=N2)=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:47]3[CH:55]=[CH:56][C:44]([O:43][CH3:42])=[CH:45][CH:46]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: COc1ccc(Cn2ccc(N)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-(4-methoxy-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methoxy-benzyl)-1H-pyrazol-3-yl]-propionamide (92 mg, 59%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O4S [M+] 515.2, found 516.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.21 (m, 2H, CH2), 1.41-1.91 (m, 8H, 4×CH2), 2.10-2.26 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 5.05 (s, 2H, NCH2), 6.66 (d, J=2.3 Hz, 1H, Ar), 6.83 (d, Jo=8.5 Hz, 2H, Ar), 7.09 (d, Jo=8.5 Hz, 2H, Ar), 7.25 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.30 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])(=[O:11])=[O:10]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccc(F)cc1F
Yield: 84.4 %

Procedure:
Prepared according to the procedure described for Example 121 using 2,4-difluorobenzenesulfonyl chloride (2.19 g, 10 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.43 g, 10 mmol), and pyridine (25 mL) to afford the product (3.532 g); m.p. 198-200° C. after trituration in hexanes/ethyl acetate (1:1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[CH:11]1([C:9]2[N:10]=[C:6]3[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:21][C:20]4[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Cc1cc(Cl)n2nc(C3CC3)nc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(C3CC3)nc2n1

Procedure:
To a suspension of Intermediate 20 (0.04 g, 0.192 mmol) in ethanol (2.5 mL), 4-(trifluoromethyl)aniline (ALDRICH, 0.031 g, 0.192 mmol) was added and the mixture was stirred under reflux for 2 h. Solvent was removed in vacuo and the crude mixture was purified by preparative HPLC (SunFire 19×150 mm, H2O 0.1% TFA-ACN 0.1% TFA gradient from 10 to 100%) to yield a beige solid which was further purified by preparative HPLC (SunFire 19×150 mm, H2O 0.1% TFA-ACN 0.1% TFA gradient from 30 to 100%) to yield the title compound as a white solid.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=O)[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH2:28]Br>C1COCC1>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:28][C:20]4[C:19](=[CH:24][CH:23]=[C:22]([N+:25]([O-:27])=[O:26])[CH:21]=4)[CH2:18]3)[CH:14]=[N:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CC1(C=Nc3ncnc(Cl)c31)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (0.29 ml, 0.74 mmol, 2.5 M) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THF (30 mL). After complete addition of butyllithium, N,N,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317(M+1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:9]=[N:8]1)(=O)C.C1COCC1.[Li+].[OH-].Cl>O>[CH3:19][C:14]1([CH3:20])[C:15]([CH3:17])([CH3:18])[O:16][B:12]([C:10]2[CH:9]=[N:8][N:7]([CH2:6][CH2:5][OH:4])[CH:11]=2)[O:13]1
Reactant: CC(=O)OCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a 50 mL roundbottom flask was charged 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl acetate (2.11 mmol, 591 mg), a solution of 2:1 THF:H2O (15 mL), and 1N LiOH(aq) (4.82 mmol, 4.82 mL). The resulting solution was stirred at room temperature for 48 hours. At 48 hours, the reaction was quenched with 1N HCl(aq) (4.82 mmol, 4.82 mL) and the solvent removed in vacuo. The product was taken forward without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1.[CH3:16]I>CN(C=O)C.O>[CH3:16][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4]1
Reactant: CI
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) was added portionwise, allowing for gas evolution, to a solution of methyl 1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C. When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (26.00 g, 96%) as an orange solid: MS (ES) m/e 190 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CS[N:16]1[CH2:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[S:18](=[O:27])(=[O:26])[NH:17]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][N:16]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[S:18](=[O:26])(=[O:27])[NH:17]2)=[N:6][CH:7]=1
Reactant: CSN1Cc2ccccc2S(=O)(=O)N1
Reactant: Cc1cc(Br)cnc1CCCCN
Product: Cc1cc(Br)cnc1CCCCNN1Cc2ccccc2S(=O)(=O)N1

Procedure:
4-(5-Bromo-3-methylpyrid-2-yl)-butylamine (0.73 g) and 3-methylthiobenzothiadiazine-1,1-dioxide (0.68 g) were fused at 130°-140° C. for 3 hours. The product was crystallised from acetonitrile to yield 3-[4-(5-bromo-3-methylpyrid-2-yl)-butylamino]benzothiadiazine-1,1-dioxide m.p. 187°-8° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:36]O.Cl>CO.O.C(Cl)Cl>[C:30]([C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@H:13]([C:15]2[O:22][NH:36][C:17](=[O:19])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 105.4 %

Procedure:
Trans-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.734 g, 1.60 mmol) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.064 g, 1.60 mmol) dissolved in water (0.500 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.098 mL, 1.60 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 4 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8 mL, 48.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.723 g, 106%) as a yellow semi-solid. MS m/z 429 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][O:46][C:47]4[C:56]5[C:51](=[CH:52][C:53]([O:57][CH3:58])=[CH:54][CH:55]=5)[N:50]=[CH:49][CH:48]=4)=[N:43][N:44]=3)[N:41]=2)[CH:33]=[CH:32][C:31]=1O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:29][C:30]1[CH:35]=[C:34]([C:36]2[CH:37]=[CH:38][C:39]3[N:40]([C:42]([CH2:45][O:46][C:47]4[C:56]5[C:51](=[CH:52][C:53]([O:57][CH3:58])=[CH:54][CH:55]=5)[N:50]=[CH:49][CH:48]=4)=[N:43][N:44]=3)[N:41]=2)[CH:33]=[CH:32][C:31]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(O)c(F)c5)nn34)ccnc2c1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(OCCN6CCOCC6)c(F)c5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(2-hydroxyethyl)morpholine (0.0964 ml, 0.788 mmol),triphenylphosphine (0.238 g, 0.909 mmol), 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenol (0.253 g, 0.606 mmol) (prepared according to General Method A) in THF (10 mL) was added DEAD (0.144 ml, 0.909 mmol). Stirred at room temperature for 1 h. Concentrated. Purified on RPHPLC. Fractions containing product were treated with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=531.2 [M+1]+. Calc'd for C28H27FN6O4: 530.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Li+].[CH3:14]C([N-]C(C)C)C.O.CCOCC>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C)c1cccnc1
Yield: 62.7 %

Procedure:
Ethyl 3-pyridylacetate (12.2 g, 73.9 mmol) in THF (30 ml) was added to LDA (81 mmol) in THF (150 ml) over 10 min at -78° C. After 1 h Mel (5.1 ml, 81 mmol) was added to the yellow suspension and the mixture brought to room temperature. H2O (300 ml) and ether (300 ml) was added, the mixture separated, and the organic layer washed with H2O and brine, dried and evaporated to give ethyl 2-(3-pyridyl)propanoate (8.3 g) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.C=O.[C:18](O)(=O)C.C(OCC)(=O)C>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C@H:9]2[CH2:13][CH2:12][N:11]([CH3:18])[CH2:10]2)=[CH:14][CH:15]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CS[C@H]2CCNC2)cc1
Agent: C=O
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@H]2CCN(C)C2)cc1
Reaction time: 0.25 h

Procedure:
750 mg of (3S)-3-(4-methoxybenzylthio)pyrrolidine [which had been prepared by neutralization of 900 mg of (3S)-3-(4-methoxybenzylthio)pyrrolidine hydrochloride, prepared as described in step (3) above, with sodium bicarbonate] were dissolved in 15 ml of dry acetonitrile, and 1.44 ml of a 35% by volume solution of formaldehyde in water was added to the solution. The reaction mixture was then stirred for 15 minutes, after which it was neutralized by the addition of acetic acid; it was then again stirred for a further 2.5 hours. At the end of this time, the reaction mixture was poured into 200 ml of ethyl acetate, and the mixture was washed with a 2N aqueous solution of potassium hydroxide and an aqueous solution of sodium chloride. The organic layer was dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluted with a 3:1 by volume mixture of ethyl acetate and methanol), to afford 349 mg of the title compound as a colorless oil.