Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(CC)CC.[C:37]1([NH:43][C:44]([C:46]2[CH:53]=[CH:52][C:49]([CH2:50]Cl)=[CH:48][CH:47]=2)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC#N>[NH2:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]1[CH2:25][CH2:26][N:27]([CH2:50][C:49]2[CH:48]=[CH:47][C:46]([C:44](=[O:45])[NH:43][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:53][CH:52]=2)[CH2:28][CH2:29]1)=[O:21]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NCC(=O)NCC1CCN(Cc2ccc(C(=O)Nc3ccccc3)cc2)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 30.2 %

Procedure:
To a mixture of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.27 g, 2.96 mmol), Et3N (1.25 mL, 8.88 mmol), KI (50 mg, 0.30 mmol) and CH3CN (200 mL) was added dropwise a solution of 4-(N-phenylcarbamoyl)benzyl chloride (800 mg, 3.26 mmol) in CH3CN (100 mL). The mixture was stirred at room temperature for 19 h and at 60° C. for 5 h. Concentration and column chromatography (SiO2, 5% CH3OH/CH2Cl2-Et3N:CH3OH:CH2C2=2:2:96) afforded 4-{(glycylamino)methyl}-1-{4-(N-phenylcarbamoyl)benzyl}piperidine (340 mg, 30%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.BrC1C=C(S(OC2C=CC(N3C(=O)CC(=O)NC4C5CCCCC=5C=CC3=4)=CC=2)(=O)=O)C=CC=1>>[N:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:33])=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: Cl
Agent: O=C1CC(=O)N(c2ccc(OS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3c(c2N1)CCCC3
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3ccncc3)cc2)c2ccc3ccccc3c2N1
Yield: 50.9 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (63 mg, 0.2 mmol) obtained in Example 1, (3), and isonicotinoyl chloride hydrochloride (71 mg, 0.4 mmol), 5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (43 mg, yield 50%) was obtained as pale green crystals in the same manner as that of Example 1, (4).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[O:27]=[C:28]1[C:33](C(Cl)=O)=[CH:32][CH:31]=[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:29]1.[N:42]1[C:51]2[C:46](=[CH:47][C:48]([NH2:52])=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[CH2:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([C:33]2[C:28](=[O:27])[O:29][C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=2)=[O:7])[C@H:9]([C:24]([NH:52][C:48]2[CH:47]=[C:46]3[C:51](=[CH:50][CH:49]=2)[N:42]=[CH:43][CH:44]=[CH:45]3)=[O:26])[CH2:10]1
Reactant: Nc1ccc2ncccc2c1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccc(Cl)c(Cl)c3)C[C@H]2C(=O)Nc2ccc3ncccc3c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 70% purity by LC/MS. MS(ESI+): m/z=621.2.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C)C=O>[Si:14]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccccc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1O
Reaction time: 3 h
Yield: 66 %

Procedure:
To a stirred solution of catechol (5.5 g; 50 mmol) in 20 mL of dimethylformamide was added imidazole (7.14 g; 105 mmol) and t-butyldimethylsilylchloride (7.53 g; 50 mmol). The reaction mixture was stirred for 3 hours after which time TLC showed the reaction to be complete. The reaction mixture was chromatographed directly onto silica gel and eluted with 5% ethyl acetate in hexane to give 7.4 g (66%) of the monosilyl catechol 16. NMR (CDCl3) δ6.963 (dd, J=8.0, 1.6 Hz, 1H, ArH), 6.891 (dt, J=8.0, 2.0 Hz, 1H, ArH), 6.847 (dd, J=8.0, 1.6 Hz, 1H, ArH), 6.773 (dt, J=7.6, 1.6 Hz, 1H, ArH), 5.518 (s, 1H, OH), 0.996 (s, 9H, CCH3), 0.252 (s, 6H, SiCH3); 13C NMR (CDCl3) δ147.250, 142.550, 122.143, 119.989, 117.835, 114.870, 25.730, 18.193, -4.322.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[S:29][C:30]([CH3:33])=[CH:31][N:32]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[S:29][C:30]([CH3:33])=[CH:31][N:32]=1)=[O:27]
Reactant: Cc1cnc(C(=O)CBr)s1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ncc(C)s2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-5-methylthiazole (Preparation is described in Example 232).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)#[N:20]>CN(C)C=O.C1CCCCC1>[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[C:5]2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2.9 g (0.06 mole) of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.4 g (0.05 mole) of 3-methyl-2-(3-pyridyl)indole in 60 ml of dimethylformamide. The reaction mixture is stirred for 0.5 hour at 0°-5° followed by dropwise addition of 9.8 g (0.05 mole) of p-cyanobenzyl bromide in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water (600 ml). The resulting solid is collected, dried, washed with petroleum ether and redissolved in ether (500 ml). The ether solution is first washed with water, then with saturated sodium bicarbonate solution, dried over MgSO4, treated with charcoal and filtered. Evaporation of the ether extract to dryness yields a yellow solid. This product is slurried in hot cyclohexane and collected by filtration to give 1-(4-cyanobenzyl)-3-methyl-2-(3-pyridyl)indole, m.p. 127°-129°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>O1CCCC1.CCCCCC>[CH2:23]([Sn:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccccc1Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a stirred solution of 3.4 g of 2-bromotoluene in 100 ml of dry tetrahydrofuran at -78° C. is slowly added 8 ml of 2.5M butyl lithium in hexane. The reaction mixture is stirred for 30 minutes and 6.5 g of tri-n-butyl tin chloride in 25 ml of tetrahydrofuran added. The reaction mixture is stirred an additional 1 hour, quenched with water and extracted with ether. The ether extract is dried over Na2SO4, filtered and the filtrate evaporated in vacuo to give 7.0 g of a residue. Mass spectrum: M+H:381.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=1)[C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:22]2[CH:21]=[C:20]([NH:19][C:3]([C:5]3[CH:6]=[CH:7][N:8]4[C:12]=3[CH2:11][S:10][CH:9]4[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:4])[CH:34]=[CH:33][CH:32]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 66 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 66° and 72° C., to a solution of 3-amino-4'-chlorobenzophenone (4.6 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 66° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 8 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 Kpa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (9.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (250 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 10° C. for 3 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (45 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(4-chlorobenzoyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.2 g) in the form of pale yellow crystals, m.p. 176° C., is thereby obtained.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=O)[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=[CH2:1])[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC1C=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Butyl lithium (3.56 mL, 1.58 M, toluene solution) was added dropwise under cooling with ice to a suspension of methyltriphenylphosphonium bromide (2.15 g, 6.03 mmol) in tetrahydrofuran (20 mL), followed by stirring at room temperature for 20 minutes, and further at 40° C. for 5 minutes. Subsequently, a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine [an isomer mixture of (4S)-form: (4R)-form (1:3)] (700 mg, 2.01 mmol) in tetrahydrofuran (7.0 mL) was added under cooling with ice to the resultant mixture, followed by stirring at room temperature for 10 hours. The reaction mixture was poured to a 10% aqueous citric acid solution (20 mL), and the resultant mixture was diluted with ethyl acetate (100 mL). The obtained aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed sequentially by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:4), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (250 mg, 36%).
Reaction SMILES: [ClH:1].[CH3:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:7][C:8]([CH3:20])([CH3:19])[CH2:9][CH2:10][N+:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12]2.C(O[Cl:26])(C)(C)C.O>CO>[CH3:2][S:3]([O-:6])(=[O:5])=[O:4].[Cl:1][N:7]([Cl:26])[C:8]([CH3:20])([CH3:19])[CH2:9][CH2:10][N+:11]12[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18]1)[CH2:15][CH2:16]2
Reactant: CC(C)(C)OCl
Reactant: Cl
Reactant: CC(C)(N)CC[N+]12CCC(CC1)CC2
Agent: CS(=O)(=O)[O-]
Solvent: CO
Solvent: O
Product: CC(C)(CC[N+]12CCC(CC1)CC2)N(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-amino-3-methylbutyl)-1-azoniabicyclo[2.2.2]octane methanesulfonate hydrochloride (0.31 g, 1.2 mmol) in methanol (4.5 mL) was cooled in an ice bath for 15 min. t-BuOCl (0.41 mL, 3 equiv, 3.48 mmol) was added in one portion via syringe to the colorless solution to give a deep yellow solution. The reaction mixture was stirred for 30 min at 0° C., and then concentrated under reduced pressure to yield a colorless oil. This oil was dissolved into water and purified via reverse phase chromatography on a Shimadzu Prep-LC utilizing water/acetonitrile and 0.05% acetic acid as modifier. Fractions were collected monitoring UV absorbance at 215 nm. Fractions were pooled and concentrated via rotovap with the water bath set at 25° C. to give a white solid, (0.21 g, 58.9%). 1H NMR (D2O, 400 MHz): δ 1.43 (s, 6H), 1.96-2.03 (m, 6H), 2.16-2.25 (m, 3H), 2.82 (s, 3 H), 3.21-3.29 (m, 2H), 3.40-3.46 (m, 6H). LRMS (ESI+) for C12H23Cl2N2+ (265.1); Found: 265, 267 (M+, M2H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[CH:12]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][S:22]([CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:29])(=[O:24])=[O:23])[CH2:17][CH2:16]1)([CH3:14])[CH3:13]>>[C:8]([Si:5]([CH3:7])([CH3:6])[O:4][CH2:3][CH2:2][N:21]([CH:18]1[CH2:19][CH2:20][N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17]1)[S:22]([CH2:25][CH2:26][NH:27][C:28]([C:30]1[S:31][C:32]([Cl:35])=[CH:33][CH:34]=1)=[O:29])(=[O:23])=[O:24])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: CC(C)N1CCC(N(CCO[Si](C)(C)C(C)(C)C)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 15 starting from 2.3 ml (3.5 equiv.) (2-bromo-ethoxy)-tert-butyl-dimethyl-silane and 1.2 g (3.05 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. 5-Chloro-thiophene-2-carboxylic acid {2-[[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(1-isopropyl-piperidin-4-yl)-sulfamoyl]-ethyl}-amide was obtained as crude material which was pure enough for further transformations.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[F-].[K+].Br[CH2:15]Br.O>CN(C=O)C>[Br:1][C:2]1[C:9]2[O:10][CH2:15][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: BrCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)c2c(c1)OCO2
Temperature: 140 °C
Yield: 60.5 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxy-benzaldehyde (1.52 g, 7.02 mmol) in DMF (20 mL), were added KF (4.077 g, 70.18 mmol) followed by dibromomethane (1 mL, 14.04 mmol) and the mixture heated at 140° C. for 4 hours. The solution was cooled to room temperature, water was added and the mixture extracted with ether. The organic layer was further washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated to give 973 mg of 7-bromo-benzo[1,3]dioxole-5-carbaldehyde. 1H NMR (300 MHz; CDCl3): δ 6.16 (s, 2H), 7.26 (s, 1H), 7.54 (s, 1H), 9.76
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:5][CH:4]=[N:3]1.O=S(Cl)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:13][C:12]1[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cn1nccc1-c1ncccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cn1nccc1-c1ncccc1CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To (2-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (182 mg, 0.96 mmol) in DCM (5 mL) was added SOCl2 (1.5 mL) at rt. The reaction mixture was stirred at rt for 4 h and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-methyl-1H-pyrazol-5-yl)pyridine (236 mg) as an off-white solid, which was used for next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[OH:21])[CH:16]=O>[Cl-].[Cl-].[Zn+2].C(OC(=O)C)(=O)C>[C:13]([O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][C:20](=[O:21])[CH3:19])/[CH:16]=[C:6]1\[CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]\1=2)(=[O:12])[CH3:14]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: Cc1cnc2c(c1)CCCC2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc(/C=C2\CCCc3cc(C)cnc32)cc1OC(C)=O

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (20 ml), 3,4-dihydroxybenzaldehyde (20 g) and acetic anhydride (50 ml) was heated at 100° for 48 hours. Further acetic anhydride (50 ml) and ZnCl2 (1 g) were added and the mixture was heated at reflux for 16 hours. The solvent was removed by evaporation, the residue was neutralised (Na2CO3) in the presence of ethyl acetate and extracted with ethyl acetate. The ethyl acetate solution was extracted with 2N HCl and this extract was washed with ethyl acetate, basified (Na2CO3) and extracted with Et2O. The ether solution was dried (MgSO4) and evaporated and the residue triturated with hexane and recrystallised from di-isopropyl ether to give the title compound (22 g) m.p. 100°-1° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[NH2:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1>[CH2:5]([O:4][C:2]([NH:8][C@@H:9]([CH:10]([CH3:12])[CH3:11])[C:13]([OH:15])=[O:14])=[O:3])[CH:6]=[CH2:7]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: C=CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Allyl chloroformate (36.2 ml, 340.59 mmol, 1.2 eq) was added dropwise to a stirred solution of L-valine (I1)(33.25 g, 283.82 mmol, 1.0 eq) and potassium carbonate (59.27 g, 425.74 mmol, 1.5 eq) in water (650 mL) and THF (650 mL). The reaction mixture was stirred at room temperature for 18 hours, then the solvent was concentrated under reduced pressure and the remaining solution extracted with diethyl ether (3×100 mL). The aqueous portion was acidified to pH 2 with conc. HCl and extracted with DCM (3×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the product as a colourless oil (57.1 g, assumed 100% yield). LC/MS (1.966 min (ES+)), m/z: 202.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.57 (br s, 1H), 7.43 (d, 1H, J=8.6 Hz), 5.96-5.86 (m, 1H), 5.30 (ddd, 1H, J=17.2, 3.4, 1.7 Hz), 5.18 (ddd, 1H, J=10.4, 2.9, 1.6 Hz), 4.48 (dt, 2H, J=5.3, 1.5 Hz), 3.85 (dd, 1H, J=8.6, 6.0 Hz), 2.03 (oct, 1H, J=6.6 Hz), 0.89 (d, 3H, J=6.4 Hz), 0.87 (d, 3H, J=6.5 Hz),
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2N=CC([N+]([O-])=O)=CN=2)[CH2:18][CH2:17]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCO[C:41]([CH3:43])=O>CO.N1C=CC=CC=1.O=[Pt]=O>[C:13]([C:10]1[N:11]=[CH:12][C:7]2[CH:6]=[C:5]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:43]=[CH:41][C:3]([NH:4][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:2][CH:1]=4)[CH2:18][CH2:17]3)[N:4]([CH2:3][C:2]([CH3:31])([CH3:32])[CH3:1])[C:8]=2[N:9]=1)#[N:14]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)Cn1c(CN2CCN(c3ncc([N+](=O)[O-])cn3)CC2)cc2cnc(C#N)nc21
Reactant: CS(=O)(=O)Cl
Agent: O=[Pt]=O
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)Cn1c(CN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc2cnc(C#N)nc21
Temperature: 25 °C
Yield: 49 %

Procedure:
To a suspension of catalytic amount of PtO2 in MeOH (20 ml) and AcOEt (20 ml), 7-(2,2-dimethyl-propyl)-6-[4-(5-nitro-pyrimidin-2-yl)-piperazin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1.15 mmol) is added and the mixture is stirred under H2 atmosphere. After being stirred for 3 h, the reaction mixture is filtered through celite and concentrated under reduced pressure to give crude amine. To a solution of the crude amine in pyridine (10 ml), methanesulfonyl chloride (1.99 mmol) is added at 0° C. and the mixture is allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture is poured into ice water and extracted with AcOEt. The combined extracts are washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; n-hexane:AcOEt=1:1) to give 296 mg of desired N-(4-{4-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-phenyl)-methanesulfonamide in 49% yield. Rf=0.52 (AcOEt only). 1H NMR (400 MHz, CDCl3) δ 1.02 (s, 9H), 2.55-2.65 (m, 4H), 2.94 (s, 3H), 3.15-3.25 (m, 4H), 3.85 (s, 2H), 4.37 (s, 2H), 6.17 (brs, 1H), 6.61 (s, 1H), 6.88 (d, 2H), 7.15 (d, 2H), 8.91 (s, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1OCOCO1.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCCl.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:10][S:11](=[O:12])(=[O:13])[NH:14][CH2:15][C:8]=2[CH:9]=1)([O-:3])=[O:2]
Reactant: C1OCOCO1
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CNS(=O)(=O)C2
Temperature: 35 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a mixture of (4-nitrophenyl)methanesulfonamide (864 mg, 4.0 mmol) and s-trioxane (120 mg, 4.0 mmol) in 1,2-dichoroethane (10 mL) was added trifluoromethanesulfonic acid (1.5 mL), followed by the addition of trifluoromethanesulfonic anhydride (1.5 mL, 4.0 mmol). The reaction mixture was stirred at 35° C. for 2 hours and refluxed overnight. The mixture was then diluted with dichloromethane (100 mL) and washed with water (100 mL) and brine (50 mL). The solvents were evaporated and the residue was purified by Prep-HPLC to give 6-nitro-3,4-dihydro-1H-benzo[d][1,2]thiazine 2,2-dioxide (210 mg, 23%) as a gray solid. MS (ES+) C8H8N2O4S requires: 228, found: 229 [M+H]+.