Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:18]([OH:21])([CH3:20])[CH3:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:21][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 10.0 g of 4-bromo-2-fluoro-1-nitrobenzene, 44.4 g of caesium carbonate and 100 ml of isopropanol is heated at 85° C. (bath) for 1 h 30, and then left to cool to ambient temperature. The mixture is concentrated under vacuum and the residue is taken up with 400 ml of water and 300 ml of ethyl acetate. The aqueous phase is extracted with 100 ml of ethyl acetate and the combined organic phases are washed twice with 200 ml of water. The organic phases are dried over magnesium sulfate and concentrated under vacuum, so as to obtain 11.59 g of crude 4-bromo-1-nitro-2-(propan-2-yloxy)benzene in the form of a yellow oil which crystallizes. TLC: Rf=0.52 (dichloromethane/heptane (1/1)).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23](=[O:26])[NH:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[C:18]([O:22][C:23]([NH:24][NH:25][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1)=[O:26])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzyl 4-oxopiperidine-1-carboxylate (4.08 g, 17.5 mmol) in 50 mL of methanol was added tert-butylcarbazate (2.31 g, 17.5 mmol). The mixture was stirred at room temperature for 3 h and then was concentrated in vacuo to afford a white foam. This residue was taken up in 50 mL of 50% glacial acetic acid. To the resulting suspension was added sodium cyanoborohydride (1.1 g, 17.5 mmol) portionwise with vigorous stirring at room temperature. After the addition was complete the mixture was stirred for 3 h at room temperature. The mixture was neutralized with 1N NaOH/solid NaOH and then extracted twice with methylene chloride. The combined organics were washed with sat'd aq sodium bicarbonate and brine, dried (Na2SO4), filtered through a pad of silica gel and concentrated in vacuo to afford Example 12A, benzyl 4-(2-(tert-butoxycarbonyl)hydrazinyl)piperidine-1-carboxylate, as a solid (6.0 g) which was pure enough to be used without purification. LRMS (ESI): 350.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].Cl[CH2:14][C:15]1[C:16]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC#N>[CH:24]([NH:23][C:16]1[C:15]([CH2:14][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=2)[C:5]#[N:6])=[CH:20][N:19]=[C:18]([S:21][CH3:22])[N:17]=1)([CH3:26])[CH3:25]
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Reactant: CSc1ncc(CCl)c(NC(C)C)n1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(CNc2cc(C#N)cc([N+](=O)[O-])c2)c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
A solution of 3-amino-5-nitrobenzonitrile (3.59 g, 22 mmol) in CH3CN (10 mL) was added dropwise to a mixture of 5-(chloromethyl)-N-isopropyl-2-(methylthio)pyrimidin-4-amine from Example A9 (5 g, 22 mmol), sodium iodide (0.33 g, 2.2 mmol), and diisopropylethylamine (2 mL, 12 mmol) in CH3CN (100 mL) at 0° C. The resultant reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was diluted with water, and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), concentrated and purified by silica gel chromatography to afford 3-((4-(isopropylamino)-2-(methylthio)pyrimidin-5-yl)methylamino)-5-nitrobenzonitrile (2.2 g, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1 H), 7.74 (s, 1 H), 7.56 (s, 1 H), 7.32 (s, 1H), 7.08 (m, 1 H), 6.63 (d, J=7.6 Hz, 1 H), 4.30 (m, 1 H), 4.15 (s, 2 H), 2.50 (s, 3 H), 1.17-1.15 (d, J=6.4 Hz, 6 H); MS (ESI) m/z: 359.2[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[H-].[Na+].I[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:15])=[CH:4][C:3]=1[F:11]
Reactant: CI
Reactant: Fc1cc2cc[nH]c2cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)c(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To the solution of 6-bromo-5-fluoro-1H-indole (0.92 g, 4.28 mmol) in dry DMF (10 mL) was added sodium hydride as 60% in oil (0.26 g, 6.41 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, and then iodomethane (0.32 mL, 5.14 mmol) was added. The mixture was stirred for 1 hour at room temperature, and then quenched with ice and extracted with EtOAc (50 mL). The organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (EtOAc-hexane, 1:9) give 6-bromo-5-fluoro-1-methyl-1H-indole as a colorless solid (0.97 g, 99%). 1H NMR (CDCl3, 400 MHz): 3.66 (s, 3H), 6.43 (d, J=2.7 Hz, 1H), 7.05 (d, J=2.7 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.4 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@@H:28]([NH2:34])[CH2:27]2>>[N:26]12[CH2:33][CH2:32][CH:29]([CH2:30][CH2:31]1)[C@@H:28]([NH:34][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH2:27]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2N[C@H]2CN3CCC2CC3)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Example 73, starting from (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (Intermediate 67) and (R)-1-azabicyclo[2.2.2]oct-3-ylamine.
Reaction SMILES: [Cl:1][CH:2]1[S:7][C:6]2[S:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:22][C:23]([F:32])([F:31])[C:24](C1NC=CN=1)=[O:25].Cl>O1CCCC1>[Cl:1][CH:2]1[S:7][C:6]2[S:8][CH:9]=[C:10]([C:24](=[O:25])[C:23]([F:32])([F:31])[F:22])[C:5]=2[C:4](=[O:11])[CH2:3]1
Reactant: O=C(c1ncc[nH]1)C(F)(F)F
Reactant: O=C1CC(Cl)Sc2sccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(Cl)Sc2scc(C(=O)C(F)(F)F)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
The compound from Step 3 (1.03 g, 5.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78° C. A solution of sodium bistrimethylsilylamide (5.0 mL of a 1.0M tetrahydrofuran solution) was added and the reaction stirred for 0.75 hours at -78° C. Trifluoroacetyl imidazole (0.68 mL, 6.0 mmol) was added and the reaction was warmed to room temperature and stirred under a nitrogen atmosphere for 16 hours. At this time, 1N hydrochloric acid (300 mL) was added to the reaction followed by extraction with ether (350 mL). The organics were washed with brine (200 mL), dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12]1.C(N(S(F)(F)[F:33])CC)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:33])[CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:12]1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=S(=O)(CC1CN(CC(O)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Solvent: ClCCl
Product: O=S(=O)(CC1CN(CC(F)c2ccc(F)cc2F)C1)c1ccc(F)cc1
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A stirred suspension of the alcohol from Step 1 (130 mg, 0.33 mmol) in dichloromethane (4 mL) under nitrogen was cooled to −10° C. (Diethylamino)sulfur trifluoride (54 μL, 0.41 mmol) was added dropwise and after 30 minutes the cooling bath was removed. After a further 15 minutes, the reaction was quenched with saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative TLC (50% ethyl acetate/isohexane) to give the title compound (64 mg, 50%). 1H NMR (500 MHz, CDCl3) δ 7.91–7.89 (2H, m), 7.40–7.34 (1H, m), 7.27–7.23 (2H, m), 6.90 (1H, t, J=8.2 Hz), 6.79 (1H, t, J=9.5 Hz), 5.70–5.58 (1H, m), 3.49 (2H, q, J=7.4 Hz), 3.38–3.36 (2H, m), 2.95 (2H, q, J=6.7 Hz), 2.90–2.70 (3H, m); m/z (ES+) 388 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[N:19]=2)([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:17]2[NH:16][C:15]([C:11]3([CH3:14])[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[N:19][C:18]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCC(C)(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Yield: 40.8 %

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.14 mmol, 60 mg) in THF (2.0 mL) was added lithium aluminum hydride (0.56 mmol, 0.56 mL of a 1M solution). The reaction was heated to reflux for 6 h, cooled, diluted with ethyl acetate (20 mL) and quenched with water (0.5 mL). The suspension was filtered and the filtrates washed with water (20 mL), dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure. The resulting solid was triturated with diethyl ether and filtered to give 20 mg of the title compound as a white powder. mp=227°-229° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31](=[O:49])[C:32]1[C:33](=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[NH:34][C:35](OC1C=CC=CC=1)=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:19]([NH:22][C:35]([NH:34][C:33]2[CH:44]=[C:45]([Cl:48])[CH:46]=[CH:47][C:32]=2[C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:49])=[O:36])(=[O:20])=[O:21])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)c2ccccc2c1O
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)c2ccccc2c1O
Yield: 73.2 %

Procedure:
From 323 mg (1.00 mmol) of 3-t-butoxycarbonyl-4-hydroxy-1-naphthalenesulfonamide and 381 mg (1.00 mmol) of 4-chloro-2-N-phenoxycarbonylanthranilic acid benzylester in a similar manner to Preparation Example 17, 447 mg (yield 73%) of 4-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-1-hydroxy-2-naphthalene carboxylic acid t-butylester (property: colorless amorphous, PMR (δppm, DMSO-d6): 1.66 (9H, s), 5.34 (3H, s), 6.98 (1H, d), 7.35-7.48 (5H, m), 7.66 (1H, m), 7.81 (1H, m), 7.89 (1H, d), 8.37 (2H, m), 8.44 (1H, s), 8.71 (1H, d), 10.02 (1H, br), 12.52 (1H, br)) was obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[Br:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Br:14][CH2:15][CH2:16][C:17]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:18]
Reactant: O=C(Cl)CCBr
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCBr)OCC(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 51.4 %

Procedure:
2,2,2-Trifluoroethanol (15 ml, 0.15 mol) and triethylamine (4.5 ml, 32.12 mmol) were added to 30 ml of dichloromethane, and cooled to 0° C. After 10 min, 2.94 ml of 3-bromopropionyl chloride (29.2 mmol) was added dropwise thereto. The mixture was warmed to room temperature and stirred for 5 hrs. After the reaction was terminated by addition of water, the mixture was extracted with ethyl acetate, and the solvent was evaporated under a reduced pressure. The solid impurities were removed by filtration to obtain the title compound as a liquid (3.53 g).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][NH2:38])[CH2:32][CH2:31]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([NH:38][CH2:37][CH2:36][N:33]3[CH2:32][CH2:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:35][CH2:34]3)=[O:3])[C:5]=12
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: NCCN1CCC(CCCCN2CCCCC2)CC1
Solvent: CC#N
Product: Cc1scc2c1N(C(=O)NCCN1CCC(CCCCN3CCCCC3)CC1)c1ccccc1NC2=O
Yield: 20 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[4-[4-(piperidin-l-yl)butyl]-piperidin-l-yl]ethanamine in a yield of 20% of theory. Colourless crystals, m.p. 186°-187° C. (acetonitrile).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][CH3:27]>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][C:18]=1[O:26][CH3:27]
Reactant: COc1cc(B(O)O)ccc1Cl
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: COc1cc(-c2c(-c3cc(C#N)ccn3)ncn2C)ccc1Cl

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-3-methoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H13ClN4O, 326. Found, 325, 327.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:6]([C:8]2[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:31]([CH3:34])(=[O:32])=[O:33])=[C:6]([C:8]2[N:13]=[C:12]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[N:11]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][OH:30])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:7]=1
Reactant: CS(=O)(=O)c1nc(-c2ccc(NC(=O)NCCO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(F)cc1-c1cc(-c2ccc(NC(=O)NCCO)cc2)nc(N2CCOCC2)n1
Yield: 5 %

Procedure:
1-(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(methylsulfonyl)pyrimidin-4-yl)phenyl)-3-(2-hydroxyethyl)urea (275 mg, 0.23 mmol), DIPEA (804, 0.46 mmol) and morpholine (1.0 mL) were heated in a Biotage microwave at 100° C. for 30 minutes. Reaction mixture was partitioned between DCM and water, the organic phase passed through a PTFE hydrophobic frit and the solvent removed in vacuo. The residue was purified further by prep HPLC (low pH) to afford 1-(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-morpholinopyrimidin-4-yl)phenyl)-3-(2-hydroxyethyl)urea (5.6 mg, 5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH:17]([N:21]3[CH:25]=[C:24]([C:26]4[C:27]5[CH:34]=[CH:33][NH:32][C:28]=5[N:29]=[CH:30][N:31]=4)[CH:23]=[N:22]3)[CH2:18][C:19]#[N:20])[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:35][N:36](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([CH2:18][CH:17]([N:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1)[CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:35]#[N:36])=[CH:7][N:6]=2)=[O:9])[CH2:11][CH2:12]1)#[N:20]
Reactant: CN(C)C=O
Reactant: N#CCC(CN1CCN(C(=O)c2ccc(Br)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#CCC(CN1CCN(C(=O)c2ccc(C#N)cn2)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 150 °C

Procedure:
Zinc cyanide (24 mg, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol) were added to a solution of 4-{4-[(5-bromopyridin-2-yl)carbonyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (15 mg, 0.029 mmol) in N,N-Dimethylformamide (0.48 mL). The mixture was degassed, then heated in the microwave at 150° C. for 15 minutes. The mixture was diluted with MeCN (1 mL), filtered and purified via preparative HPLC-MS, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH (9 mg, 67%). 1H NMR (400 MHz, d6-dmso): δ □12.12 (br s, 1H), 9.03 (dd, 1H), 8.81 (s, 1H), 8.68 (s, 1H), 8.43 (dd, 1H), 8.37 (s, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 6.97 (d, 1H), 4.99 (tt, 1H), 3.62-3.56 (m, 2H), 3.27-3.19 (m, 4H), 2.86 (dd, 1H), 2.82 (dd, 1H), 2.64-2.56 (m, 1H), 2.53-2.41 (m, 2H), 2.39-2.31 (m, 1H); LCMS (M+H)+: 467.3.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:12]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)C(=O)[O:18][N:17]=2)=[N:13][O:14][N:15]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[Cl:28][C:23]1[CH:22]=[C:21]([NH:20][C:16]([C:12]2[C:11]([CH2:10][CH2:9][NH:8][S:31]([CH3:30])(=[O:33])=[O:32])=[N:15][O:14][N:13]=2)=[N:17][OH:18])[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
To a solution of 3-[4-(2-amino ethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (16.0 mg, 0.037 mmol) in DCM (1.0 mL) was added TEA (15 μL, 0.11 mmol) and methanesulfonyl chloride (4.2 μL, 0.055 mmol). The resulting mixture was stirred at rt for 1 h and then the solvent was removed under reduced pressure. The residue was dissolve in MeOH (1 mL) and 2.0 M sodium hydroxide in water (0.10 mL) was added. After stirring for 4 h, the reaction solution was diluted with MeOH and a few drop of acetic acid and then purified by preparative LCMS to give the desired product as a white solid (14.1 mg, 78.3%). MF=C12H13ClFN5O4S; LCMS calculated C12H14ClFN5O4S (M+H)+: m/z=377.0.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].O>[Fe].CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ccc(SCc2ccccc2)cc1N

Procedure:
2.4 G. of 1-acetamido-2-nitro-4-benzylthiobenzene is treated with 2.4 g. iron powder and 1.2 g. ferrous sulfate in a mixture of 60 ml. water and 240 ml. methanol, at reflux for 4 hours. The mixture is then filtered, the filtrate concentrated and the residue recrystallized from benzene. Pure 1-acetamido-2-amino-4-benzylthiobenzene is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6](S(C)(=O)=O)=[C:5]([N+:11]([O-:13])=[O:12])[N:4]=[C:3]1[CH2:14][OH:15].[C-:16]#[N:17].[K+].CS(C)=O>O>[CH3:1][N:2]1[C:6]([C:16]#[N:17])=[C:5]([N+:11]([O-:13])=[O:12])[N:4]=[C:3]1[CH2:14][OH:15]
Reactant: Cn1c(CO)nc([N+](=O)[O-])c1S(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(CO)nc([N+](=O)[O-])c1C#N

Procedure:
2.21 G. (0.01 moles) of 1-methyl-2-hydroxymethyl-4-nitro-5-methylsulfonylimidazole and 0.715 g. of potassium cyanide in 20 ml. of dry dimethylsulfoxide are heated at 100°C. for 30 minutes. The reaction mixture is diluted with an equal volume of water and extracted with ethyl acetate. The combined extracts are dried and evaporated to dryness affording an oily residue which is recrystallized from isopropanol affording 1-methyl-2-hydroxymethyl-4-nitro-5-cyanoimidazole, m.p. 122° to 124°C.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[C:10](=[O:16])[C:9](=[N:17]O)[CH2:8]2.C1(C)C=CC(S(Cl)(=O)=[O:26])=CC=1>O>[C:9]([CH2:8][C:7]1[CH:6]=[C:5]([O:4][CH3:3])[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[C:10]([OH:16])=[O:26])#[N:17]
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=NO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(CC#N)c(C(=O)O)c(OC)c1
Temperature: 50 °C
Yield: 70 %

Procedure:
To a solution of NaOH (3.4 g, 85 mmol) in H2O (50 ml) was added of 5,7-Dimethoxy-indan-1,2-dione 2-oxime (5.0 g, 22.6 mmol). The mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (5.7 g, 30 mmol) was added in portions to the mixture. The mixture was heated at 80° C. for 15 min. After cooling carefully to room temperature, the precipitate (a little) was removed from the mixture. Mother liquid was acidified by concentrated HCl to PH=3-4 and precipitate was formed. The precipitate was collected and dried to give product (3.5 g, 70%). LC-MS: m/e 220 (M−1).
Reaction SMILES: [ClH:1].Cl.[N:3]1[NH:4][N:5]=[N:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=1.[SH:16][CH2:17][C:18](O)=O>Cl>[ClH:1].[N:6]1[NH:5][N:4]=[N:3][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:18]([CH2:17][SH:16])=[N:15][C:10]=2[CH:9]=1
Reactant: O=C(O)CS
Reactant: Nc1ccc(-c2nn[nH]n2)cc1N
Agent: Cl
Product: SCc1nc2cc(-c3nn[nH]n3)ccc2[nH]1
Temperature: 110 °C
Yield: 56.8 %

Procedure:
To 4-(2H-tetrazol-5-yl)-benzene-1,2-diamine dihydrochloride (9.40 g, 37.7 mmol) in 50% (v/v) hydrochloric acid (105 ml). 2-mercaptoacetic acid (2.4 ml, 3.18 g, 34.5 mmol) was added and the reaction mixture heated under nitrogen at 110° C. for 48 hours. Additional mercaptoacetic acid (0.5 ml, 0.66 g, 7.20 mmol) was added after 24 hours. The reaction mixture was cooled and a sample analysed by hplc. The greenish coloured solid was filtered off and washed with water. The solid was dried at 50° C. under a vacuum (90 mBar) to yield [5-(2H-tetrazol-5-yl)-1H-benzoimidazol-2-yl]-methanethiol hydrochloride (5.27 g, 65% yield), Rt=7.4 mins, purity by HPLC>97%. 1H NMR (d6-DMSO, 400 MHz) 8.49 ppm (1H, m), 8.22 ppm (1H, dd, 8.8 Hz, 1.6 Hz), 7.95 ppm (1H, m, 9.2 Hz), 4.67 ppm (0.3H, s), 4.24 ppm (2H, s). MS: (Electrospray+) 233.0 m/z (M+H), 463.0 m/z (2M−H).