Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:11]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[CH3:1])=[O:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2c(C)[nH]c3ccccc23)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 51.5 %

Procedure:
To a solution of 2-methyl-1H-indole-3-carboxylic acid (3.3 g, 18.85 mmol), 1-hydroxybenzotriozole (4.69 g, 37.7 mmol, 2 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.24 g, 37.7 mmol, 2 eq), triethylamine (20.0 mL) in dichloromethane (100 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (5.77 g, 37.7 mmol, 2 eq). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography (silica gel, dichloromethane/methanol=10:2) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-methyl-1H-indole-3-carboxamide as a white solid (3.00 g, 9.7 mmol, 51%). LRMS (M+H+) m/z: calcd 309.36. found 310. HPLC Purity (214 nm): >95%. 1H NMR (300 MHz, d6-DMSO): δ 11.61 (s, 1H), 11.43 (s, 1H) 7.74 (d, J=5.1 Hz, 1H), 7.58-7.54 (m, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.04 (t, J=6 Hz, 3H), 5.89 (s, 1H), 4.32 (d, J=4.5 Hz, 2H), 2.57 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.C(C=P(CCCC)(CCCC)CCCC)#N>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@H:7]1[CH2:11][CH2:10][C@H:9]([N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[CH2:8]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1CC[C@H](c2ccccn2)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](c2ccccn2)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A solution of trans-3-(2-pyridyl)cyclopentanol (957 mg, 5.86 mmol) in THF (25 mL) was cooled to 0° C. and treated with phthalimide (1.29 g, 8.77 mmol), cyanomethylenetri-n-butylphosphorane (2.12 g, 8.78 mmol). The reaction mixture was stirred at 70° C. for 8 h. The solvent was removed, and the crude product was purified by column chromatography (Hexane/EtOAc=3/1→1/1) and triturated with Hexane-EtOAc to yield cis-N-[3-(2-pyridyl)cyclopentyl]phthalimide (901 mg, 53%) as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.S1(=O)(=O)C2C=CC=CC=2C(=O)N1.[F:26][C:27]([F:32])([F:31])[C:28](O)=[O:29].FC(F)(F)S(O)(=O)=O>>[F:26][C:27]([F:32])([F:31])[C:28]([O:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1NS(=O)(=O)c2cccc(O)c21
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1NS(=O)(=O)c2cccc(OC(=O)C(F)(F)F)c21

Procedure:
The specification describes a process for preparing 4-hydroxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, a sweetener, from 1,2-benzisothiazol-3(2H)-one-1,1-dioxide by anodic oxidation in the presence of trifluoroacetic acid or trifluoromethanesulfonic acid and, optionally, in the presence of salts which increase the conductivity. The oxidation is effected in an anhydrous medium and the 4-trifluoroacetoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide formed as an intermediate when, for example, trifluoroacetic acid is used is decomposed with water to obtain the desired end product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[CH3:13][O:14][CH2:15][CH2:16]O.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][O:14][CH2:15][CH2:16][O:12][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH2:1])=[CH:3]2
Reactant: COCCO
Reactant: Nc1ccc2c(O)cccc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cccc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 219.2 %

Procedure:
6-Aminonaphthalen-1-ol (100 mg, 0.63 mmol) was dissolved in THF (6 mL), and 2-methoxyethanol (96 mg, 1.26 mmol), DEAD (635 μL, 1.26 mmol), and triphenylphosphine (330 mg, 1.26 mmol) were added thereto. The resulting mixture was stirred at room temperature for 4 hours and then concentrated. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give 5-(2-methoxyethoxy)naphthalen-2-ylamine (300 mg, quantitative) as a wax-like material.
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41]C3CCCCO3)=[CH:33][CH:32]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24]C3CCCCO3)=[CH:16][CH:15]=2)[CH:13]=1.Cl>CO.O>[OH:41][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:10]2[CH:9]=[C:8]([OH:7])[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=3)[CH:11]=2)=[CH:36][CH:35]=1
Reactant: COCCOCOc1cc(-c2ccc(OCCCOC3CCCCO3)cc2)cc(-c2ccc(OCCCOC3CCCCO3)cc2)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCCCOc1ccc(-c2cc(O)cc(-c3ccc(OCCCO)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.90 g (12.1 mmol) 3′-[5′-(2-methoxy-ethoxymethoxy)-[1,1′:3′,1″-terphenyl]-4,4″-diylbis(oxy-3,1-propanediyloxy)]bis(tetrahydro-2H-pyrane) are dissolved in 60 ml methanol, and, after addition of 9 ml conc. hydrochloric acid, stirred overnight at RT. The mixture is diluted with water and extracted three times with MTB ether. The combined organic layers are washed with sat. aq. sodium chloride solution and dried over sodium sulfate. 4,4″-Bis-(3-hydroxy-propoxy)-[1,1′;3′,1″]terphenyl-5′-ol is obtained as a yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[CH:13]=[C:14]([NH:18][C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[O:25][C:21]=3[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>C1COCC1.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[C:14]([N:18]([C:19]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:22]3[C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[O:25][C:21]=3[CH:20]=2)[S:44]([CH3:43])(=[O:46])=[O:45])[CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(Nc3cccc(Br)c3)c(C3CC3)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(Br)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 37.5 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1M in THF) (1.93 mL, 1.93 mmol) was added dropwise to a solution of ethyl 6-((3-bromophenyl)amino)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (734 mg, 1.48 mmol) in THF (10 mL) at −78° C. The mixture was stirred for 45 minutes and then a solution of methanesulfonyl chloride (0.463 mL, 5.94 mmol) in THF (1.5 mL) was added at −78° C. After complete addition the reaction mixture was allowed to warm to room temperature overnight. Water and EtOAc were added. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane:EtOAc) to give ethyl 6-(N-(3-bromophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-3-carboxylate (318 mg, 37%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (s, 1H) 8.03-8.13 (m, 2H) 7.62-7.66 (m, 1H) 7.59 (s, 1H) 7.43 (s, 4H) 7.30-7.39 (m, 1H) 4.26-4.41 (m, 2H) 3.42 (s, 3H) 2.12-2.26 (m, 1H) 1.28-1.37 (m, 3H) 0.71-1.14 (m, 4H) 0.41 (m, 1H). %). LCMS (m/z, ES+)=572, 574 (M+H, M+2).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)C>[OH-].[Na+]>[NH:15]([C:8]1[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[CH:6][C:7]=1[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Nc1ccccc1

Procedure:
A solution of ethyl-4-anilino-3-benzylamino-5-sulphamyl-benzoate (1 g) in 1N sodium hydroxide (15 ml) was heated on a steam bath for 1 hour. After cooling, the 4-anilino-3-benzylamino-5-sulphamyl-benzoic acid was precipitated by addition of acetic acid, collected and recrystallized from 60% ethanol in water. The melting point was 248°-249° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Mg]Cl)(C)C.[Br:12][C:13]1[S:17][C:16]([C:18](=[O:24])[CH2:19][CH2:20]C(O)=O)=[CH:15][CH:14]=1.C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[Br:12][C:13]1[S:17][C:16]([C:18](=[O:24])[CH2:19][CH2:20][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:15][CH:14]=1
Reactant: N#CCC(=O)O
Reactant: O=C(O)CCC(=O)c1ccc(Br)s1
Agent: CC(C)[Mg]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#CCC(=O)CCC(=O)c1ccc(Br)s1
Yield: 69 %

Procedure:
To a solution of 2-cyanoacetic acid (13 g, 50 mmol) in THF (100 mL) was added dropwise i-PrMgCl (16 g, 250 mmol) at −78° C. for 1 h. A solution of 4-(5-bromothiophen-2-yl)-4-oxobutanoic acid (8A) and CDI (12 g, 74 mmol) in THF was added dropwise at −78° C. and the resultant mixture was stirred at −78° C. for 1 h and at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (200 mL). The organic phase was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford 8B as a black oil (9.7 g, 69%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][C:20](O)=[O:21])=[C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][N:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[CH2:19][CH2:18][C:17]2[C:13]([CH3:12])=[N:14][O:15][C:16]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CCc2c(C)noc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of methyl 4-aminobenzoate (0.47 g), 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.60 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.50 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.61 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-methoxycarbonylphenyl)-3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.75 g, yield 79%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 140–141° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)=[O:13])=[C:8]([N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[CH:7]=1)=[CH2:5])C.[Br:31]N1C(=O)CCC1=O>O1CCCC1.O>[N:26]1([C:8]2[CH:7]=[C:6]([C:4](=[O:5])[CH2:3][Br:31])[CH:11]=[CH:10][C:9]=2[C:12](=[O:13])[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[CH:30]=[N:29][CH:28]=[N:27]1
Reactant: C=C(OCC)c1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(-n2cncn2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)c2ccc(C(=O)CBr)cc2-n2cncn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In the same manner as in the synthesis of Compound 515, 1,2,4-triazole was added to Compound 21 of Reaction 6. Then, tributyl(1-ethoxyvinyl)tin was added to the mixture, and the resulting mixture was reacted to obtain (4-(1-ethoxyvinyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone. Thus obtained (4-(1-ethoxyvinyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone was dissolved in a mixed solution of tetrahydrofuran and water (1/1), and N-bromosuccinimide (NBS) was added thereto. The mixture was stirred for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with EtOAc. The organic layer was washed with a saturated aqueous Na2 SO3 solution, water, and brine. The extracted organic layer was dried over anhydrous MgSO4, and the solid substance was filtered off. The filtrate was vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO2, n-Hex/EA=3/1→1/2) to obtain 1-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone. Thus obtained 1-(3-(1H-1,2,4-triazol-1-yl)-4-(3,4,5-trimethoxybenzoyl)phenyl)-2-bromoethanone (65 mg, 0.14 mmol) was dissolved in 3 ml of 95% ethanol, and thiourea (16 mg) was added thereto. The mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and vacuum evaporated to remove the solvent. The resulting residue was purified by column chromatography (SiO2, CH2Cl2/MeOH=30/1→10/1) to obtain Compound 516 (29.3 mg, 48%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:18]=O)[CH:13]=[N:14][C:15]=1[O:16][CH3:17].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:18][NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[CH:13]=[N:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ncc(C=O)cc1F
Reactant: Nc1cccc(F)n1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(CNc2cccc(F)n2)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To 6-fluoro-pyridin-2ylamine (14, 1.50 g, 13.4 mmol) in 52.9 mL of acetonitrile, 5-fluoro-6-methoxy-pyridine-3-carbaldehyde (23, 2.00 g, 12.9 mmol), triethylsilane (10.6 mL, 66.3 mmol), and trifluoroacetic acid (5.3 mL, 69.0 mmol) were added. The reaction was stirred at 80° C. overnight, then concentrated under vacuum, combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as white solid (24, 3.21 g).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:23])[C:16]3[N:17]=[CH:18][C:19]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: OB(O)c1ccncc1
Reactant: CN(c1ccc(I)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc(-c2ccncc2)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C

Procedure:
Under N2, a mixture of (R)—N-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-5-iodo-N-methylpyridin-2-amine (90.0 mg, 0.21 mmol), pyridin-4-yl boronic acid (28.4 mg, 0.23 mmol), PdCl2dppf.CH2Cl2 (17.2 mg, 0.02 mmol) and K2CO3 (0.058 g) in DMF (5.0 mL) was stirred at 110° C. for 16 h. It was then cooled to ambient temperature, diluted with water (5.0 mL) and extracted with ethyl acetate (3×10 mL). The combined extracts was washed with brine (3×5.0 mL), dried over Na2SO4 (anhydrous), filtered and concentrated. The residue was purified by flash chromatography to give the title product. MS (m/z): 372 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][NH:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:39][S:40](Cl)(=[O:42])=[O:41]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH:28]([OH:38])[CH2:29][N:30]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CNCc4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(O)CN(Cc4ccccc4)S(C)(=O)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-{4′-[4-(3-benzylamino-2-hydroxy-propyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and methanesulfonyl chloride.
Reaction SMILES: [CH2:1]([C:3]([N:8]=[C:9]=[N:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C([N:21]=[C:22]=[N:23]C1C=NC=CC=1)(C)(C)C>>[C:22]([N:23]=[C:9]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[NH:8][C:3]([CH2:4][CH3:5])([CH2:6][CH3:7])[CH2:1][CH3:2])#[N:21]
Reactant: CCC(CC)(CC)N=C=Nc1cccnc1
Reactant: CC(C)(C)N=C=Nc1cccnc1
Product: CCC(CC)(CC)NC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure in Example 1, but substituting N-(1,1-diethylpropyl)-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the N"-cyano-N-(1,1-diethylpropyl)-N'-3-pyridylguanidine was obtained with a melting point of 192.5°-193.5° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCI
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCN1CCC(C(N)=O)CC1
Yield: 59.8 %

Procedure:
Prepared from isonipecotamide (3.3, 25.7 mmol), 1-iodopentane (5.1 g, 25.7 mmol) and potassium carbonate (3.54 g, 25.7 mmol) according to the procedure used for Example 8 (Step A) to give 3.05 g of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(NS(C)(=O)=O)cc2CC1
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.56 ml) was added dropwise to a solution of 7-amino-3-tertiary-butoxycarbonyl-1,2,4,5-tetrahydro-3H-3-benzazepine (1.9 g) in pyridine (40 ml) cooled to 0°. Stirring was continued at room temperature for 18 hours. The solvent was removed by evaporation to give an oil which was taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine, then dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%). The product-containing fractions were combined and evaporated in vacuo to give a semi-solid which was triturated with ether to give the title compound, yield 1.2 g, m.p. 153°-154°.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]O)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(CCO)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Reaction time: 1.5 h
Yield: 17.3 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (300 mg, 0.88 mmol), (prepared as described for the starting material in Example 7), 2-(4-acetylpiperazin-1-yl)ethanol (183 mg, 1.06 mmol) and triphenylphosphine (278 mg, 1.06 mmol) were stirred together in dichloromethane (10 ml) and the mixture cooled in an ice/water bath. Diisopropyl azodicarboxylate (209 μl, 1.06 mmol) was added and the mixture stirred for 1.5 hours. A further one mole equivalent of 2-(4-acetylpiperazin-1-yl)ethanol (172 mg, 1 mmol), triphenylphosphine (262 mg, 1 mmol) and diisopropyl azodicarboxylate (197 μl, 1 mmol) were added and the mixture stirred for a further 1 hour. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give a crude solid that was further purified by preparative HPLC to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (75 mg, 17%).