Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[O:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:7]1[CH2:6][CH2:5][C:4]2([O:3][C:2](=[O:1])[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=3)[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OC(=O)Nc1ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccccc2C2(CCNCC2)O1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.7 %

Procedure:
tert-Butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate (6.71 g, 21.1 mmol) was dissolved in dichloromethane (50 mL), treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 45 min. The reaction was concentrated under reduced pressure, re-dissolved in acetonitrile and re-concentrated under reduced pressure. The crude TFA salt was cooled in an ice-H2O bath, dissolved in ice-cold saturated brine (20 mL) and H2O (50 mL) and basified with ice-cold 35% NaOH (aq). A small amount of product (obtained from extraction with 50 mL ethyl acetate) was added to the aqueous layer to initiate crystallization. The suspension obtained was cooled in an ice-H2O bath, filtered, rinsed with ice-cold H2O and dried to afford 3.071 g spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one free base as a white crystalline solid. An additional 800 mg free base was obtained via extraction of the mother liquor with ethyl acetate (10×50 mL) and subsequent trituration of the crude free base with acetonitrile (overall yield=84%). LC/MS m/z 219.2 [M+H]+, retention time 0.58 min (RP—C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, DMSO-d6) δ 10.17 (br s, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.87 (dd, J=8.2, 1.2 Hz, 1H), 2.89 (m, 2H), 2.82 (m, 2H), 1.84 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:12]=3[N:11]=2)=[N:2]1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:28][NH:29][C:19]([C:17]2[CH:16]=[CH:15][C:13]3[NH:14][C:10]([C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)=[N:11][C:12]=3[CH:18]=2)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Product: O=C(NCC1CCCCC1)c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1

Procedure:
Starting with 20 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid and 18.7 ml of cyclohexylmethylamine, 16.1 mg of 2-(1H-indazol-3-yl)-1H-benzimidazole-5-carboxylic acid N-cyclohexylmethyl)amide are obtained in the form of a white powder.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:22])=[O:14])[CH:4]=1)=O.[Cl-].[C:24]([C:26]1([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH2+:29][CH2:28][CH2:27]1)#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClC(Cl)C>[C:24]([C:26]1([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([C:13]([NH:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]3[OH:22])=[O:14])[CH:4]=2)[CH2:28][CH2:27]1)#[N:25]
Reactant: N#CC1(c2ccncc2)CC[NH2+]CC1
Reactant: O=Cc1cc(C(=O)N[C@H]2CCCC[C@@H]2O)nc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: N#CC1(c2ccncc2)CCN(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (0.035 g, 0.117 mmol) in 0.50 mL dichloroethane was added 4-cyano-4-(pyridin-4-yl)piperidinium chloride (0.032 g, 0.141 mmol), sodium triacetoxyborohydride (0.037 g, 0.176 mmol), and triethylamine (0.016 mL, 0.117 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The resultant residue was subjected to purification via reverse phase HPLC. The isolated material was then purified via preparative TLC (7% MeOH/CH2Cl2) to afford the titled compound that gave a mass ion (ES+) of 470.2551 for M+H+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].COC1C=C(OC)C=CC=1C[NH2:27]>C(O)C>[NH2:27][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc2c1=O

Procedure:
To the yellow solution of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (500 mg, 1.57 mmol) in ethanol (0.5 ml) is added 2,4-dimethoxybenzylamine (4.72 ml, 31.4 mmol) under argon. The solution is heated at 150° in a closed vial in a microwave reactor for 4 minutes. After removal of the solvent and 2,4-dimethoxybenzylamine by high-vacuum rotavapor evaporation the remaining deep purple oil is treated with diethyl ether to obtain a suspension, which is filtered and dried to yield the crude title compound as a deep purple solid, m.p. 232-237° C.
Reaction SMILES: C([N:3](CC)CC)C.[Al+3].[Cl-].[Cl-].[Cl-].[N+]([C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][O:20][C:21]2=[O:22])=[CH:17][CH:16]=1)([O-])=O.CCOC(C)=O>ClCCCl>[OH:20][CH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:24][C:23]=1[C:21]([NH2:3])=[O:22]
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Reactant: CCN(CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)c1ccccc1CO
Temperature: 17.5 °C
Yield: 30.6 %

Procedure:
A solution of triethylamine (TEA, 0.658 g, 0.91 ml, 6.50 mmol, 1.5 equiv.) in 1,2-dichloroethane (3 ml) was added dropwise under stirring and cooling with ice to a suspension of AlCl3 (0.635 g, 4.76 mmol, 1.1 equiv.) in 1,2-dichloroethane (7 ml). The temperature was maintained at 15-20° C. during the addition and the mixture was then allowed to warm up at room temperature. A solution of 1-dimethoxytrityl-6-amino-hexan-1-ol (16) (2.00 g, 4.76 mmol, 1.1 equiv., prepared as described by Woo and Fung (1996), International Pat. App. Pub. No. WO 96/05215) and 6-nitrophthalide (18) (0.766 g, 4.33 mmol, 1.0 equiv.) in 1,2-dichloroethane (3 ml) was added over a period of 20 min and the mixture was stirred at room temperature overnight. The completion of the reaction was confirmed by TLC analysis (EtOAc containing 1% TEA). The reaction mixture was then quenched with an ice-water mixture (30 ml) and stirred for an additional 30 min. The resulting suspension was filtered through a bed of Celite® and the filter cake was washed with 1,2-dichloroethane (10 ml). The organic phase of the combined filtrates was separated, washed with water (30 ml) and brine (20 ml), dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (35-75% EtOAc in hexanes, gradient elution) yielding 0.20 g (8%) of compound (20) as a pale yellow oil. Rf=0.2 (hexanes/EtOAc 1:1, v/v, containing 1% TEA). 1H NMR (300 MHz, CD3CN) δ 8.32-8.27 (m, 2H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 2H), 7.33-7.20 (m, 8H), 6.87 (d, J=9.1 Hz, 4H), 4.69 (d, J=5.9 Hz, 2H), 4.14 (t, J=5.9 Hz, 1H), 3.77 (s, 6H), 3.35 (q, J=6.5 Hz, 2H), 3.03 (t, J=6.4 Hz, 2H), 1.64-1.55 (m, 4H), 1.43-1.28 (m, 4H). 13C NMR (75 MHz, CD3CN) δ 167.4, 158.8, 147.7, 145.9, 136.9, 130.1, 128.2, 128.0, 126.9, 125.1, 122.9, 113.2, 85.8, 63.3, 62.3, 55.1, 39.8, 29.8, 29.1, 26.7, 26.0.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([NH2:12])[C:9]([NH2:11])=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1.C(O[C:16]([S-])=[S:17])C.[K+].C(O)(=O)C>O>[NH:11]1[C:9]2[CH:10]=[C:5]3[CH2:4][O:3][CH2:2][O:1][C:6]3=[CH:7][C:8]=2[N:12]=[C:16]1[SH:17]
Reactant: Nc1cc2c(cc1N)OCOC2
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Sc1nc2cc3c(cc2[nH]1)COCO3
Reaction time: 1 h
Yield: 81.3 %

Procedure:
21.2 g of 1,3-benzodioxane-6,7-diamine was dissolved while heating in 300 ml of alcohol, then diluted with 75 ml of water, treated with 23.6 g of potassium ethylxanthate and boiled under reflux overnight. Subsequently, there were added thereto 300 ml of water and at 60°-70° C. 20 ml of glacial acetic acid. After stirring at this temperature for 1 hour, the suspension was cooled, suction filtered and washed with water. 21.6 g (81.2% of theory) of 1,8-dihydro-m-dioxino(5,4-f)benzimidazole-2-thiol of melting point 288°-289° C. were obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH3:39][S:40]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([CH:27]([CH3:29])[CH3:28])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:13]2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCNCC4)CC3)cccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1nc2c(C(=O)NCC3CCN(CC4CCN(S(C)(=O)=O)CC4)CC3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2-Isopropyl-1H-benzoimidazole-4-carboxylic acid (1-piperidin-4-ylmethylpiperidin-4-ylmethyl)amide (40 mg, 0.1 mmol) was dissolved in N,N-dimethylforinamide (1.0 mL) at room temperature. To this solution was added N,N-diisopropylethylamine (0.175 mL, 1 mmol) followed by methanesulfonyl chloride (11.5 mg, 0.1 mmol). The mixture was stirred at room temperature for 16 h, then concentrated in vacuo and the residue purified by preparative reverse-phase HPLC to afford the bis trifluoroacetate salt of the title compound as a white solid (27.2 mg, 0.04 mmol, 40%). (m/z): [M+H]+ calcd for C24H37N5O3S 476.27; found 476.2. Retention time (anal. HPLC: 2-65% MeCN/H2O over 4 min)=1.66 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=1)[C:9](Cl)=[O:10])(=[O:3])[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=1)[C:9]([NH:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)Cl
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc(C(C)=O)ccc1OCC

Procedure:
The title compound was prepared from 5-acetyl-2-ethoxybenzoyl chloride and 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide following the procedure of Preparation 6, and was obtained as a white solid (60%), m.p. 225°-227° C. Found: C,61.35; H,6.25; N,15.07. C19H24N4O4 requires C,61.28; H,6.50; N,15.04%.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][P:8]([CH3:12])(=[O:11])[O:9][CH3:10].C[O:14][C:15](=O)[CH2:16][CH2:17][CH:18]=[C:19]([Cl:21])[CH3:20].C(O)(=O)C>O1CCCC1>[CH3:6][O:7][P:8]([CH2:12][C:15](=[O:14])[CH2:16][CH2:17][CH:18]=[C:19]([Cl:21])[CH3:20])(=[O:11])[O:9][CH3:10]
Reactant: COC(=O)CCC=C(C)Cl
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCC=C(C)Cl)OC
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
21.8 ml of n-butyllithium solution (2.2M in hexane) are added dropwise at -65° C. to a solution of 5.58 g of methanephosphonic acid dimethyl ester in 160 ml of absolute tetrahydrofuran and the mixture is stirred at that temperature for 15 minutes. A solution of 4.05 g of the methyl ester obtained in Example (6d) in 10 ml of tetrahydrofuran is then added and the mixture is stirred at -65° C. for 1 hour. The solution is heated to -10° C., 2.80 ml of acetic acid are added and the mixture is concentrated. The residue is partitioned between ethene and water, the ether phase is separated, dried over magnesium sulphate and concentrated in vacuo. The residue is then purified by ball-tube distillation. 4.23 g of the title compound are obtained (bath temperature 180°-185° C., 1.5 torr).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[H-].[Na+].Br[CH2:31][C:32]([C:34]1[S:35][CH:36]=[CH:37][CH:38]=1)=[O:33]>O1CCCC1>[C:34]1([C:32]([CH2:31][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[CH2:4][CH:3]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:2]2=[O:1])=[O:33])[S:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Reactant: O=C(CBr)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1cccs1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was dissolved in tetrahydrofuran (10 ml), 60% sodium hydride (0.16 g) was added thereto under argon atmosphere, and the mixture was stirred for 30 minutes at room temperature. A solution of 2-bromoacetylthiophene (0.99 g) in tetrahydrofuran (1 ml) was added to the resultant mixture, stirred for 2 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate, the organic layer was washed succesively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), to thereby obtain 1.01 g of the titled compound (Yield: 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(O)(=O)C>[OH:9][C:4]1[CH:3]=[C:2]([N:1]2[C:13](=[O:14])[C:12]3[C:11](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]2=[O:15])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(N)cc(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)cc(N2C(=O)c3ccccc3C2=O)c1
Yield: 80.6 %

Procedure:
36.0 g (292 mmol) 3-amino-5-methylphenol and 73.5 g (496 mmol) phthalic acid anhydride were heated for 2 h to boiling under reflux in 280 ml glacial acetic acid. Water was added, it was heated for a short time, allowed to cool and filtered. 59.6 g (80%) 2-(3-hydroxy-5-methyl-phenyl)-isoindole-1,3-dione of Fp 174°-175° C. was obtained.
Reaction SMILES: [C:1]12[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3[C:14]1=[C:5]([C:6]1[C:11]([CH:12]=3)=[N:10][CH:9]=[CH:8][CH:7]=1)[CH:4]=[CH:3][CH:2]=2.[N+:20]([O-])([O-:22])=[O:21].[Na+].O>S(=O)(=O)(O)O>[N+:20]([C:3]1[CH:2]=[C:1]2[C:18](=[O:19])[O:17][C:15](=[O:16])[C:13]3=[CH:12][C:11]4[C:6]([C:5]([CH:4]=1)=[C:14]23)=[CH:7][CH:8]=[CH:9][N:10]=4)([O-:22])=[O:21]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1OC(=O)c2cc3ncccc3c3cccc1c23
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C1OC(=O)c2cc3ncccc3c3cc([N+](=O)[O-])cc1c23
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
As above for example 2, part A, 8-azaphenanthrene-1,10-dicarboxylic anhydride (7.62 g, 30.6 mmol) was nitrated in concentrated sulfuric acid (30 mL) at 110° C. by the addition of sodium nitrate (6.50 g, 76.5 mmol) in five portions over 31 h. The acid solution was poured into water (300 mL), rinsing the residue from the reaction flask with water (4×25 mL). The aqueous suspension was neutralized to about pH 4 with concentrated sodium hydroxide solution and sodium acetate (5 g) was added as a buffer. The precipitated solid was collected on a frit and dried. The crude material was heated at reflux in acetic acid (70 mL) and acetic anhydride (10 mL) for 4 h and the suspension was cooled to room temperature. The brown solid was collected on a frit, washed with acetic acid (20 mL), and dried to give 5.94 g (66%) of the nitro compound: mp >300° C.; 1H NMR (CDCl3, 300 MHz) δ 7.97 (dd, 1H, J=9.0, 4.5 Hz), 9.16 (d, 1H, J=9.0 Hz), 9.33 (d, 1H, J=4.5 Hz), 9.42 (s, 1H), 9.48 (d, 1H, J=1.5 Hz), 9.87 (d, 1H, J=1.5 Hz); MS (CI, CH4) m/e (%) 295 (M+H+, 100), 250 (4), 121 (6), 103 (4), 93 (19).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1)#[N:18]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]#[N:18])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: N#Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2cccc(C#N)c2)cc1-c1c(Br)cnn1C
Yield: 61.5 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 3-cyanophenyl isocyanate (0.020 g, 0.14 mol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 21 (0.032 g, 0.08 mmol, 58%) as a white powder. LCMS m/z (%)=426 (M+H79Br, 99), 428 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.45 (s, 1H), 8.26 (d, J=9.6 Hz, 1H), 8.05 (t, J=1.7 Hz, 1H), 7.74 (dd, J=1.5, 8.2 Hz, 1H), 7.70 (dd, J=2.7, 9.0 Hz, 1H), 7.50 (s, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 3.83 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].N>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
4-Fluorobenzene-1,2-diamine (2 g, 15.86 mmol) was dissolved in THF (49.4 ml) and 1,1′-Carbonyldiimidazole (2.83 g, 17.44 mmol) was added at RT. The reaction mixture was stirred overnight at RT. To this was added concentrated ammonia solution (1.5 ml) and the mixture stirred for 30 minutes and then diluted with water (100 ml). The resultant solid was collected by filtration, washed with water, followed by Et2O and then dried in vacuo to afford 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.250 g, 52%); 1H NMR (400 MHz, DMSO-d6) 6.66-6.79 (2H, m), 6.81-6.94 (1H, m), 10.64 (1H, s), 10.76 (1H, s); m/z: (ES+) MH+, 151.19. b) A solution of 5-fluoro-1H-benzo[d]imidazol-2(3H)-one (1.25 g, 8.22 mmol) in phosphorus oxychloride (25.2 ml, 270.34 mmol) was heated for 18 hours at 100° C. The reaction mixture was cooled to RT and excess of POCl3 was evaporated in vacuo. The residue was neutralized with saturated NaHCO3 solution (10 ml) and extracted with EtOAc (3×20 ml). The organic phase was washed with brine and then dried over MgSO4, filtered and concentrated under reduced pressure to afford 2-chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 82%); 1H NMR (400 MHz, DMSO-d6) 7.09 (1H, ddd), 7.36 (1H, dd), 7.53 (1H, dd); m/z: (ES+) MH+, 171.34. c) 2-Chloro-6-fluoro-1H-benzo[d]imidazole (1.146 g, 6.72 mmol) was charged to high pressure autoclave PV10832 (Parr 160 ml) with methylamine 40% EtOH solution (50 ml, 6.72 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 13 bar. The reaction mixture was evaporated and the residue dissolved in MeOH and added to an SCX column. The desired product was eluted from the column using 7M NH3/MeOH. Fractions containing product were evaporated and the residue was purified by flash chromatography on silica, eluting with a gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to afford 6-fluoro-N-methyl-1H-benzo[d]imidazol-2-amine (0.707 g, 64%); 1H NMR (400 MHz, DMSO-d6) 2.27 (3H, d), 6.38-6.44 (2H, m), 6.67 (1H, dd), 6.79-6.84 (1H, m); m/z: (ES+) MH+, 166.31.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].I[CH2:12][CH3:13]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:12][CH3:13])[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(Br)ccc1=O
Reaction time: 0.5 h

Procedure:
A solution of 5-bromopyridin-2-ol (1.74 g, 10.00 mmol) in DMF (20 ml) was treated with NaH at room temperature and then stirred for 30 min. Iodoethane (0.823 ml, 12.00 mmol) was added to the mixture and the reaction was stirred overnight at room temperature. The reaction was diluted with DCM, washed with water, dried over Na2SO4, and concentrated to dryness via rotary evaporation to provide the title compound as a crude product which was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([S:25][CH:26]2[CH2:31][O:30]C(C3C=CC=CC=3)[O:28][CH2:27]2)[N:12]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:22][CH2:23][CH2:24]2)(=[O:20])=[O:19])[CH:14]=[C:13]([S:25][CH:26]([CH2:27][OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: O=S(=O)(Nc1cc(SC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cc(SC(CO)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
A solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)thio]pyrimidin-4-yl]azetidine-1-sulfonamide (the product of step ii) (0.11 g) and pyridinium para-toluenesulfonate (99 mg) in methanol (5 mL) and H2O (2 drops) was heated at 60° C. for 1 h. The solution was cooled and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with H2O, dried (MgSO4) and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with EtOAc/iso-hexane (8:2) to give the subtitle product as a yellow gum. The gum was dissolved in DCM and methanol, filtered through charcoal and the filtrate evaporated under reduced pressure. The residual solid was dried under high vacuum at 40° C. to give the title product as a white solid. Yield: 50 mg
Reaction SMILES: C(OCC)(=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C([O:21][C:22](=[O:32])[CH2:23][CH:24]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25](O)=O)(C)(C)C>C1COCC1>[CH2:28]([CH:24]1[CH2:25][O:32][C:22](=[O:21])[CH2:23]1)[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
Ethyl acetate (0.12 mL, 1.22 mmol) in THF (2 mL) was added dropwise to a stirring solution of lithium bis(trimethylsilyl)amide (1.22 mL of a 1 M solution in THF, 1.22 mmol) at −78° C. under argon. After 20 minutes, 3 (0.21 g, 1.16 mmol) in THF (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (3 mL) and allowed to warm to room temperature. The mixture was diluted with ether (20 mL) and dilute hydrochloric acid (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with ether (2×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 99:1) to give the nitro-ester 4 (0.13 g, 41%) as a colorless liquid; Rf(heptane/ethyl acetate, 9:1) 0.32; νmax(film)/cm−1 1731 (C═O), 1547 (NO2), 1375 (NO2); δH (400 MHz; CDCl3): 4.73 (2H, s, CH2NO2), 4.14 (2H, q, J=7.1, CO2CH2Me), 2.58 (2H, s, CH2CO2Et), 2.07 (2H, m), 1.71–1.66 (4H, m), 1.60–1.24 (8H, m), 1.26 (3H, t, J=7.2, CO2CH2Me); m/z (ES+) 270 (M+H, 100%).