Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1.[OH-:26].[Na+].[O-]Cl.[Na+]>C(OCC)(=O)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:12][S+:11]([O-:26])[C:9]2[NH:8][C:7]3[CH:23]=[CH:24][C:4]([O:3][CH:2]([F:1])[F:25])=[CH:5][C:6]=3[N:10]=2)[C:18]=1[O:19][CH3:20]
Reactant: COc1ccnc(CSc2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: [OH-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Temperature: -10 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A flask equipped with a stirrer is charged with ethyl acetate (140 ml). Under mixing, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl) methyl]thio]-1H-benzimidazole VI (5 g, 13.6 mmol) is added to the flask followed by 18.8% aq. NaOH (11.5 ml, d=1.16 g ml−1, 4.9 eq.). The reactor is cooled to −10° C. 9.7% NaOCl (9.7 ml, d=1.16 g ml−1, 1.04 eq.) is added dropwise over 15 min. The two-phase mixture is stirred at room temperature for 3 h. The phases are then separated, and 27% aq. sodium metabisulfite (Na2S2O5) (7 ml) is added to the aqueous phase to quench unreacted oxidant. The organic phase is washed with water, and the aqueous phase is washed twice with ethyl acetate. The organic phases are combined, dried over sodium sulfate (Na2SO4), and evaporated under 20 mm Hg vacuum. The resulting oil is triturated with methyl t-butyl ether and filtered to obtain pantoprazole (3.7 g, yield 71%) which contains 0.04% sulfone and 0.03% compound VI as within the limit of UV detection.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].O>O1CCOCC1>[CH3:11][C:12]([CH3:16])([CH3:15])[CH2:13][O:14][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)COCc1ccc(C#N)cc1
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Add sodium bis(trimethylsilyl)amide (3 mL, 6 mmol, 2M solution in THF) to a solution of 2,2-dimethyl-1-propanol (528 mg, 6 mmol) in anhydrous 1,4-dioxane. Stir until the suspension becomes homogenous. Then add a solution of 4-cyanobenzyl bromide (980 mg, 5 mmol) in anhydrous 1,4-dioxane (3 mL). Heat the mixture in a microwave oven at 100° C. for 30 min. Cool to room temperature, add water (50 mL) and extract with EtOAc (3×50 mL). Dry the combined organic extracts over MgSO4, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (95:5 to 1:1 gradient) to obtain the desired intermediate (811 mg, 80%).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH3:15])[CH2:10][C:11]([O:13]C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[K+]>CO>[Si:1]([O:8][CH:9]([CH3:15])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(C)O[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(CC(=O)O)O[Si](C)(C)C(C)(C)C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a solution of 3.58 g (15.4 mmol) of methyl (-)-3-t-butyldimethylsilyloxybutyrate dissolved in 30 ml of methanol, 30 ml of 1N potassium hydroxide was added and the mixture was stirred for 15 hours. After almost all methanol was distilled away, the resultant was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was washed with a saturated solution of NaCl, dried with anhydrous magnesium sulfate and concentrated under reduced pressure to give 3.18 g of (-)-3-t-butyldimethylsilyloxybutyric acid (yield: 95%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]#[N:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[OH-:28].[K+].O>CC(O)(C)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([NH2:27])=[O:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: [OH-]
Reactant: Cc1nccn1-c1ccc(Sc2cccc(C3(C#N)CCOCC3)c2)cc1
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nccn1-c1ccc(Sc2cccc(C3(C(N)=O)CCOCC3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
4-{3-[4-(2-Methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}-tetrahydro-pyran-4-carbonitrile (27.35 g) were dissolved in t-BuOH (280 mL) at 50° C. To the solution, KOH (12.28 g) was added and the mixture was stirred overnight. The suspension was cooled to room temperature and water (180 mL) was added. The suspension obtained was filtered and the filtercake was dried at 50° C. to yield 4-{3-[4-(2-Methyl-imidazol-1-yl)-phenyl sulfanyl]-phenyl}tetrahydro-pyran-4-carboxylic acid amide (17.52 g, 55% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]#[N:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC#N)c3=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (70 mg, 0.14 mmol) in dry DMF (1 ml) was added potassium carbonate (57 mg, 0.41 mmol) and bromoacetonitrile (29 μl, 0.41 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 35% EtOAc in cyclohexane) to give the title compound (45 mg, 60%). 1H NMR (500 MHz, CDCl3): 8.43 (1H, s), 7.26-7.19 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.72 (2H, s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]([CH3:16])[CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[F:34].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:20]2[CH2:19][CH2:18][N:17]([CH:13]([C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[C:6]([NH:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:23])[CH:14]([CH3:16])[CH3:15])[CH2:22][CH2:21]2)=[O:30])=[CH:27][C:26]=1[F:34]
Reactant: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCNCC1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCN(C(=O)c2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of N-tert-butyl-3-(2-methyl-1-(piperazin-1-yl)propyl)benzamide (13.6 mg, 0.043 mmol), 4-amino-3-fluorobenzoic acid (10 mg, 0.065 mmol), N-ethyl-N-isopropylpropan-2-amine (11 mg, 0.086 mmol) and 1-propanephosphonic acid cyclic anhydride (55 mg, 0.086 mmol, 50% solution in ethyl acetate) in dichloromethane (2.0 mL) was stirred at room temperature for 2 hours. The mixture was treated with strong cation exchange column chromatography and purified with silica column chromatography (eluting with 33% ethyl acetate in heptane then 66% ethyl acetate in heptane) to afford the title compound (11.8 mg).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:28])[C@H:10]([NH2:27])[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[N:32]=[CH:33][N:34]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[CH2:1]([O:8][C@H:9]([CH3:28])[C@H:10]([NH:27][C:30]1[N:38]=[CH:37][N:36]=[C:35]2[C:31]=1[NH:32][CH:33]=[N:34]2)[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](OCc1ccccc1)[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 96.1 %

Procedure:
A mixture of (1R,2R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (100 mg, 0.27 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (65 mg, 0.27 mmol) and DIPEA (240 μL, 1.35 mmol) in n-butanol (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford the title compound (128 mg, 96%). LCMS (Method J): RT 3.19 min [M+H]+ 494.1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][NH:18][C:17](=[O:20])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Br)[CH:26]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:18]2[CH2:19][CH:15]([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:8]=3)[CH2:16][C:17]2=[O:20])[CH:26]=1)[CH3:22]
Reactant: CCOC(=O)c1cccc(Br)c1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC1CCCC1
Product: CCOC(=O)c1cccc(N2CC(c3ccc(OC)c(OC4CCCC4)c3)CC2=O)c1
Yield: 66.5 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-pyrrolidin-2-one (300 mg, 1.1 mmol) and 3-bromobenzoic acid ethyl ester (303 mg, 1.32 mmol) was treated according to General Procedure I to provide 310 mg of the desired product as a white solid. Yield: 67%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:25][C:26](=[O:32])[C:27](OCC)=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH2:23][CH3:24])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(=O)C([NH:71][CH2:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=2[O:80][CH3:81])=O)C=CC=1OC1C=CN=C2C=C(C3C=CC(OCCN4CCOCC4)=C(OC)C=3)SC=12>>[CH2:23]([N:21]1[CH:22]=[C:18]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:25][C:26](=[O:32])[C:27]([NH:71][CH2:72][CH2:73][C:74]4[CH:79]=[CH:78][CH:77]=[CH:76][C:75]=4[O:80][CH3:81])=[O:28])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:19]=[CH:20]1)[CH3:24]
Reactant: COc1ccccc1CCNC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)c(OC)c4)sc23)c(F)c1
Reactant: CCOC(=O)C(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CC)cn4)sc23)c(F)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)C(=O)NCCc5ccccc5OC)cc4F)c3s2)c1
Yield: 90 %

Procedure:
Starting from the amino ester 142 and following the same procedure as described for the synthesis of compound 136 (example 52, scheme 40), title compound 141 was obtained as white solid in 90% yield. 1H NMR (DMSO-d6) δ (ppm): 11.04 (s, 1H), 9.06 (t, J=6.4 Hz, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.02 (dd, J=2.4 and 12.8 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.84-7.78 (m, 1H), 7.79 (d, J=1.2 Hz, 1H), 7.67 (s, 1H), 7.52 (t, J=5.2 Hz, 1H), 7.20 (td, J=1.6 and 8.0 Hz, 1H), 7.14 (dd, J=1.6 and 7.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.87 (t, J=7.2 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 4.06 (q, J=7.2 Hz, 2H), 3.79 (s, 3H), 3.42 (q, J=7.2 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 1.40 (7.2 Hz, 3H). MS (m/z): 560.2 (M+H).
Reaction SMILES: [ClH:1].[C:2](N)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC[O-].[Na+].[CH3:15][N:16]([CH2:18][C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([NH:24][NH2:25])=O)[CH3:17].Cl.CCOCC>C(O)C>[ClH:1].[CH3:15][N:16]([CH3:17])[CH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:21]([C:22]2[N:9]=[C:2]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:25][N:24]=2)[CH:20]=1
Reactant: N=C(N)c1ccccc1
Reactant: CN(C)Cc1cccc(C(=O)NN)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CN(C)Cc1cccc(-c2n[nH]c(-c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred ethanolic suspension of benzamidine hydrochloride salt (235 mg, 1.5 mmol, 1.5 eq.), was added 1.2N NaOEt in ethanol (1.7 ml, 2 eq.) over 3 minutes, the mixture was further stirred for 30 min. at r.t. To this was added 3-dimethylaminomethyl-benzoic acid hydrazide (193 mg, 1 mmol) in ethanol at 20° C. and the mixture heated to reflux for 24 hrs. Upon cooling the product mixture was filtered, solvent evaporated and residue subjected to preparative reversed-phase HPLC purification using a YMC ODS-AQ column (20×50 mm) and a (0.1% trifluoroacetic acid) water-acetonitrile gradient (25 ml/min. flow rate). The pure fractions were concentrated and the product obtained was converted to the hydrochloride salt by addition of excess 2N HCl/ether solution (1.0 ml) followed by solvent evaporation and high vacuum drying to afford the title compound (84 mg, 0.27 mmol, 27% yield) as a yellow foam. MS: m/e=279.4 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:27]4[CH2:28][CH2:29][O:30][CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNCC1CNCCO1
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCO1

Procedure:
By the use of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(ethylaminomethyl)morpholine, the reaction is similarly carried out as Example 11 to give 1-cyclopropyl-7-[2-(ethylaminomethyl)morpholino]6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, melting at 210°-213° C. with decomposition.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]1[NH:13][C:14]1[C:19]([CH:20]2[CH2:22][CH2:21]2)=[N:18][C:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[C:16]([CH:31]2[CH2:33][CH2:32]2)[N:15]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH:20]1([C:19]2[C:14]([NH:13][C@@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:12][C@H:4]3[NH2:1])=[N:15][C:16]([CH:31]3[CH2:32][CH2:33]3)=[C:17]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:18]=2)[CH2:21][CH2:22]1
Reactant: [N-]=[N+]=N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of N-[(1R,2R)-2-azido-2,3-dihydro-1H-inden-1-yl]-3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-amine (0.55 g, 1.15 mmol) in anhydrous THF (30 mL) was added PPh3 (0.396 g, 1.51 mmol). The resulting mixture was stirred at rt for 3 hr. To the solution was added water (0.25 mL, 13.9 mmol). The reaction is then allowed to stir overnight at rt. The mixture is concentrated, and the resulting solid is dissolved in MeOH. Purify by passage over Biorad acidic resin by applying the MeOH solution onto the resin and rinsing the resin with MeOH. The resin was then rinsed with 5% triethylamine/MeOH solution to afford 0.52 g (75%) of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine as a solid: 1H NMR (CDCl3) δ 0.85-1.12, 1.64-1.76, 1.89, 2.68-2.82, 3.31-3.39, 3.66-3.72, 5.16, 5.33, 7.28-7.53; MS (ESI+) for C25H24Cl2N4 m/z 451 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:8]([S:10]([N:13]([CH2:27][C:28](Cl)=[O:29])[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=2)[O:17][C:16]([CH3:26])([CH3:25])[CH2:15]1)(=[O:12])=[O:11])[CH3:9]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C(Cl)Cl>[CH2:8]([S:10]([N:13]([CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=2)[O:17][C:16]([CH3:25])([CH3:26])[CH2:15]1)[CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)=[O:29])(=[O:11])=[O:12])[CH3:9]
Reactant: Nc1ccncc1
Reactant: CCS(=O)(=O)N(CC(=O)Cl)C1CC(C)(C)Oc2ccc(F)cc21
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)N(CC(=O)Nc1ccncc1)C1CC(C)(C)Oc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
141 mg of p-aminopyridine and a spatula tipful of DMAP dissolved in 6 ml of pyridine are treated with a solution of 655 mg of [ethanesulfonyl-(6-fluoro-2,2-dimethylchroman-4-yl)amino]acetyl chloride in 6 ml of methylene chloride. The mixture is stirred at RT for 4 h and then concentrated in vacuo. The product is partitioned between EA and water and the organic phase is washed with water. After removing the solvent in vacuo, 600 mg of the product are obtained as a colorless foam (m.p. 195° C.).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(O)(=O)C>O>[C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Yield: 100 %

Procedure:
A mixture of 4.0 g sodium 4-[[2-(phenylmethyl)benzoyl]amino]benzoate is suspended in water and the pH adjusted to 5 with acetic acid. The solid is collected by filtration and dried at 80° C. in vacuo to give 3.75 g of the desired product, 246°-247° C. M+ =332.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Mg].[CH3:9][O:10][CH2:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O>C(OCC)C>[CH3:9][O:10][CH2:11][CH2:12][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccsc1Br
Reactant: COCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Mg]
Solvent: CCOCC
Product: COCCc1sccc1C
Temperature: 25 °C
Yield: 36.9 %

Procedure:
Some drops from a solution of 2-bromo-3-methylthiophene (1.5 g, 8.5 mmol) in dry diethyl ether was added to a suspension of magnesium (308 mg, 12.7 mmol, 1.5 equiv.) in dry diethyl ether until the Grignard reagent began to form and the mixture started to reflux. The remaining solution was added dropwise. A solution of toluene-4-sulfonic acid 2-methoxy-ethyl ester (2.9 g, 12.7 mmol, 1.5 equiv.) in dry diethyl ether was added dropwise at room temperature, and the mixture was refluxed for two hours. After cooling to room temperature, the mixture was quenched with saturated ammonium chloride solution and extracted with tert. butylmethyl ether. The combined organic extracts were washed with water, brine, dried over magnesiumsulfate-dihydrate, filtered and evaporated to give a yellow oil. After purification on silica gel, 490 mg of the title compound were obtained as a light yellow oil. GC-MS (EI): M=156
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:30][CH2:31][O:32][CH3:33]>C(OCC)(=O)C>[CH3:19][O:18][CH2:17][CH2:16][O:15][C:3]1[C:2]([O:1][CH2:30][CH2:31][O:32][CH3:33])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCBr
Reactant: COCCOc1c(O)cc([N+](=O)[O-])cc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOc1cc([N+](=O)[O-])cc(C(=O)OC)c1OCCOC
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a mixture of methyl 3-hydroxy-2-{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate (4.4 g, 16.2 mmol), potassium carbonate (4.5 g, 33 mmol) and acetonitrile (100 mL) was added 1-bromo-2-(methyloxy)ethane (2.5 mL, 24 mmol). The resulting mixture was heated at reflux 18 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (100 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed (silica gel, 30-50% ethyl acetate-hexane) to provide to give methyl 2,3-bis{[2-(methyloxy)ethyl]oxy}-5-nitrobenzoate, (4.9 g, 14.8 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): 8.27-8.26 (d, 1H), 7.92-7.91 (d, 1H), 4.37-4.35 (m, 2H), 4.27-4.25 (m, 2H), 3.94 (s, 3H), 3.83-3.81 (m, 2H), 3.77-3.74 (m, 2H), 3.45 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1Cl)=[O:5])C.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:4](=[O:5])[C:6]3=[N:7][NH:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[C:15]3=[N:27]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1ccc(-n2nc3c4c([nH]nc-3c2=O)CCCC4)cc1
Yield: 12.8 %

Procedure:
4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), 4-methoxyphenylhydrazine hydrochloride (0.37 g) and potassium carbonate (0.29 g) in xylene were heated under reflux for 3 h. The solid was collected by filtration, washed with hexane, then water. The residue was absorbed onto silica and purified by flash chromatography using a gradient elution: CH2Cl2 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 99:1 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 98:2 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 97:3 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 96:4 (250 ml), CH2Cl2/(MeOH/NH3 10:1) 95:5 (250 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (79 mg, 13%). δH (360 MHz; DMSO) 1.83 (4H, m, CH2), 2.67 (2H, t, J=5.3 Hz, CH2), 2.72 (2H, d, J=5.3 Hz, CH2), 3.78 (3H, s, OCH3), 7.02 (2H, d, J=9 Hz, ArH), 8.06 (2H, d, J=9 Hz, CH2), m/z (ESP+) 297 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:7][CH2:6][CH2:5]2.[O-:19][C:20]#[N:21].[Na+]>C(O)(=O)C.O>[C:12]1([C:11]2[NH:21][C:20](=[O:19])[NH:1][C:2]3[C:10]=2[CH:9]=[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:3]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc2c(cc1C(=O)c1ccccc1)CCC2
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)c2cc3cccc3cc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of 5-amino-6-benzoylindane (160 mg, 0.68 mmol) in 6 mL of acetic acid and 0.6 mL of water was added sodium cyanate (53 mg, 0.81 mmol) and the solution was stirred at rt for 3 h. Water was then added to produce a suspension which was filtered and washed with water. The resulting solid was dried under vacuum to give the title compound (139 mg, 79%). 1H NMR (CDCl3): 13.25 (bs,1H), 7.80 (d, 2H), 7.70 (s,1H), 7.60 (m, 4H), 3.05 (t, 2H), 2.95 (t, 2H), 2.15 (p, 2H).