Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][C:19](OC)=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCOCC.CCCCCC>C(Cl)Cl>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]=[O:20])=[C:8]2[CH3:23])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc2c(c1)c(CC=O)c(C)n2Cc1ccc(Br)cc1
Temperature: -78 °C
Yield: 87.7 %

Procedure:
To a solution of ester from Step 2 (16.0 g, 39.8 mmol) in CH2Cl2 (320 mL) at -100° C. was added slowly a solution of DIBAH (1.5M/toluene, 32 mL, 47.7 mmol). The reaction was then stirred for 1-- h at -78° C., before being quenched by the addition of MeOH (3 mL), followed by 25% w/v tartaric acid (100 mL). After stirring overnight at r.t., the product was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered, and evaporated to give a pale green syrup. This was stirred vigorously with 1:4 Et2O/hexane to give 13 g of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.C(N(CC)CC)C.[Cl:28][CH2:29][CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH:16]1([N:13]2[CH2:14][CH2:15][N:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([CH2:2][NH:1][S:32]([CH2:31][CH2:30][CH2:29][Cl:28])(=[O:34])=[O:33])[CH:20]=[CH:19][C:6]=4[N:7]=3)[CH2:11][CH2:12]2)[CH2:17][CH2:18]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NCc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(CCCCl)NCc1ccc2nc(N3CCN(C4CC4)CC3)sc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
To a solution of 6-aminomethyl-2-(4-cyclopropylpiperazin-1-yl)benzothiazole (500 mg, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (879 mg, 8.2 mmol). The mixture was stirred at 0° C. for 5 min and then 3-chloropropane-1-sulfonyl chloride (308 mg, 1.74 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 h and then allowed gradually to reach rt. Then the mixture was stirred for another 1 h at rt. The volatiles were evaporated and the residue was extracted with CH2Cl2. This afforded a crude product, which was purified by column chromatography on silica gel (elute: 5% CH2Cl2 in methanol) to give 3-chloro-propane-1-sulfonic acid [2-(4-cyclopropylpiperazin-1-yl)benzothiazol-6-ylmethyl]amide 300 mg (39.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N)c(F)c1
Yield: 98.9 %

Procedure:
In 100 ml of ethanol was dissolved 3 g of 2-(3-fluoro-4-nitrophenyl)propionic acid. To the solution was added 0.25 g of 5% palladium on charcoal to conduct catalytic hydrogenation. The catalyst was filtered off and the solvent was evaporated off under reduced pressure to afford 2.55 g of 2-(4-amino-3-fluorophenyl)propionic acid as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[C:4]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH:3]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:32]2[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]2)=[O:17])[CH2:12][CH2:13]1)=[O:27]
Reactant: O=C(O)CC1CCN(c2ccc(Cl)cc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CC(=O)N2CCC(O)CC2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
A mixture of 0.100 g (0.246 mmol) of {1-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-piperidin-4-yl}-acetic acid, 0.124 g (1.23 mmol) of 4-hydroxypiperdine, 0.10 g (0.32 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.10 mL (0.74 mmol) of triethylamine in N,N-dimethylformamide (3 mL) are stirred at room temperature for 3 hours. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse phase HPLC to provide 0.040 g (33%) of the title compound (278) as a colorless solid. [M+H]+=490.2.
Reaction SMILES: [CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:13]=[CH:14][C:8]=2[S:7](=[O:22])(=[O:21])[N:6]=1)([CH3:3])[CH3:2].Cl>[OH-].[Na+]>[CH:1]([NH:4][C:5]1[NH:10][C:9]2[CH:11]=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=[CH:14][C:8]=2[S:7](=[O:21])(=[O:22])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)NC1=NS(=O)(=O)c2ccc(CC(=O)O)cc2N1
Yield: 84.6 %

Procedure:
Ethyl (3-isopropylamino-1,1-dioxo-1,4-dihydro-1λ6,2,4-benzothiadiazin-6-yl)acetate (0.22 g) was stirred in 5 ml of 4M aqueous sodium hydroxide at room temperature for 1 h. The reaction mixture was then acidified with 4M hydrochloric acid. The resulting precipitate was collected by filtration, the filter cake was rinsed with a small amount of water and dried to give 0.17 g of the title compound, m.p. 262-264° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].S(O[CH2:25][CH:26]1[CH2:31][CH2:30][CH:29]=[CH:28][O:27]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:25][CH:26]2[CH2:31][CH2:30][CH:29]=[CH:28][O:27]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(OCC2CCC=CO2)cc1
Reaction time: 4.5 h
Yield: 78.1 %

Procedure:
A solution of 831 mg of 4-acetamidophenol in 5 ml of dimethylformamide was stirred for 30 minutes at room temperature with 240 mg of 55% sodium hydride. 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran was then added and the mixture was heated, with stirring, at 90°-95° C. for 4.5 hours. The mixture was then poured into water and extracted with diethyl ether. The ethereal extract was washed with water and dried over anhydrous magnesium sulphate, after which the solvent was evaporated off. The residue was purified by column chromatography through silica gel, to give 965 mg of the title compound, melting at 114°-116° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:24]3[C:16](=[CH:17][N:18]=[C:19]4[C:23]=3[CH:22]=[CH:21][N:20]4S(C3C=CC=CC=3)(=O)=O)[N:15]=[N:14]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CO.C1COCC1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:24]3[C:16](=[CH:17][N:18]=[C:19]4[C:23]=3[CH:22]=[CH:21][NH:20]4)[N:15]=[N:14]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](n2nnc3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.6 %

Procedure:
A mixture of racemic trans [3-(6-benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester (2.00 g, 4.14 mmol), aqueous sodium hydroxide solution (10.4 mL, 20.7 mmol, 2M), methanol (30 mL) and THF (50 mL) was stirred at ambient temperature for 45 minutes. DCM was added and the solution washed (water and brine) and concentrated to dryness. Purification by column chromatography on silica gel (gradient: DCM to ethyl acetate) afforded 902 mg (64%) of racemic trans [3-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclopentyl]-carbamic acid tert-butyl ester as an off white solid. LCMS (Method B, ESI): RT=3.21 min, m+H=343.3; 1H NMR (400 MHz, DMSO) δ: 12.34 (s, 1H), 8.99 (s, 1H), 7.60 (d, 1H), 7.18 (d, 1H), 7.03 (d, 1H), 5.64 (m, 1H), 4.23 (m, 1H), 2.47 (m, 2H, partially obscured by DMSO), 2.20 (m, 3H), 1.70 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][S-:2].[Na+].F[C:5]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:6]=1[C:7]#[N:8].O>CS(C)=O>[I:13][C:10]1[CH:11]=[CH:12][C:5]([S:2][CH3:1])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(I)ccc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(I)cc1C#N
Yield: 93.4 %

Procedure:
Sodium thiomethoxide (0.142 g) was added to a solution of 2-fluoro-5-iodobenzonitrile (0.5 g) in DMSO (1 mL) and the mixture stirred. An exotherm was noted. After stirring for 90 min, water was added and the solid that precipitated was collected, washed with water and dried at 50° C. under vacuum to leave the subtitle compound as an off-white solid (0.52 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][CH:7]1[CH:11]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:10][O:9][CH2:8]1.[Br-].[Na+].CC1(C)N([O])C(C)(C)CCC1>CCOC(C)=O.C1(C)C=CC=CC=1.O>[CH2:16]([O:15][C:13]([NH:12][CH:11]1[CH2:10][O:9][CH2:8][C:7]1=[O:6])=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(NC1COCC1O)OCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1COCC1=O)OCc1ccccc1

Procedure:
A solution of bleach (100 ml), containing sodium bicarbonate (7.34 g), was added dropwise to a rapidly stirred mixture of 3-hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran (21 g, 88 mmol), sodium bromide (9.4 g), TEMPO (50 mg) in EtOAc (140 ml), toluene (140 ml) and water (40 ml). After a persistant orange colour developed the mixture was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate, brine and dried (MgSO4). Evaporation under reduced pressure and purification of the residue by column chromatography afforded the title compound as white crystals, 18 g, 87%.
Reaction SMILES: Br[C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1C(C1C=CC(Cl)=CC=1)O.CN(C)CC(O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[F:47][C:48]([F:57])([F:56])[C:49]1[CH:50]=[C:51]([OH:55])[CH:52]=[CH:53][CH:54]=1>O1CCOCC1.CC(=O)OCC.O.[Cu]I>[CH3:22][N:6]1[C:5]2[N:23]=[CH:24][C:2]([O:55][C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([C:48]([F:47])([F:56])[F:57])[CH:50]=3)=[CH:3][C:4]=2[C:9](=[O:10])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:7]1=[O:21]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)cnc21
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: 100 °C
Yield: 34.8 %

Procedure:
To a mixture of 6-bromo-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 20, step 4, 500 mg, 1.26 mmol), N,N-dimethylglycine (65 mg, 0.631 mmol), CuI (30 mg, 0.158 mmol) and Cs2CO3 (821 mg, 2.52 mmol) in dioxane (10 mL) was added 3-(trifluoromethyl)phenol (306 mg, 1.89 mmol). The reaction was heated at 100° C. for 18 h followed by heating at 120° C. for 8 h, cooled to RT then diluted with EA (50 mL) and water (20 mL). The organic layer was washed with water (2×20 mL) and brine (20 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (6:1) to give 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (210 mg, 35% yield) as a white solid. LCMS: [M++Na] 502 and TR=1.626 min.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9][CH3:10].BrC1C2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])C=2)[N:14]([Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:13]=1.C(I)C>C1COCC1>[C:32]([Si:29]([CH3:31])([CH3:30])[N:14]1[C:15]2[C:7](=[CH:6][C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[C:8]([CH2:9][CH3:10])=[CH:13]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(Br)cn2[Si](C)(C)C(C)(C)C
Reactant: CCCCC
Agent: [Li]C(C)(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A 1.5 M solution of tert-butyllithium in pentane (3.3 ml, 4.99 mmol) was added dropwise to a solution of 3-bromo-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1 g, 2.3 mmol) in THF (6 ml) at −78° C. under an argon atmosphere. After 15 min ethyl iodide (0.37 ml, 4.5 mmol) was added at −78° C. The reaction mixture was stirred for 30 min at −78° C. and for 2 h at RT. After quenching with saturated aqueous NaHCO3 solution the reaction mixture was partitioned between ether and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 880 mg (2.26 mmol, 99%) 1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-3-ethyl-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5](I)=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)#[CH:11]>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([C:11]#[C:10][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[CH:4][N:3]=1
Reactant: Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1cc(C#Cc2cnc(Br)cc2N)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
4-Amino-2-bromo-5-iodopyridine (5) (2.58 g 8.63 mmole), copper(I) iodide (164 mg 0.86 mmole) and bis(triphenylphosphine)palladium dichloride (216 mg 0.432 mmole) were weighed into a 100 mL flask and DMF (25 mL) with triethylamine (22 mL) was added. The mixture was stirred at r.t. for 15 minutes under nitrogen. 4-Ethynyl-1-methyl-1H-pyrazole (20) (945 mg at 100%, 8.91 mmole) in DMF (10 mL) and triethylamine (5 mL) was added to the flask. The reaction was stirred at r.t. for 1.75 hrs. The reaction was diluted with ethyl acetate (450 mL) and the solution was washed with water (3×240 mL), brine (120 mL), dried and evaporated. The residue was flash chromatographed (silica/ethyl acetate) to give the title compound (2.11 g, 88%). 1H-NMR (CDCl3, 500 MHz): δ 3.94 (s, 3H), 4.80 (br s, 2H), 6.79 (s, 1H), 7.59 (s, 1H), 7.66 (s, 1H), 8.15 (s, 1H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][C:6]([C:13]([OH:15])=[O:14])=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:9]2[C:4](=[N:5][C:6]3[C:13](=[O:14])[O:15][C:10](=[O:12])[C:7]=3[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1cc2occc2nc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2nc3ccoc3cc21

Procedure:
Furo[3,2-b]pyridine-5,6-dicarboxylic acid (3.3 g, 0.0159 mol) in acetic anhydride (100 mL) is heated to 70°-80° C. for six hours. The reaction mixture is cooled, filtered and the solid is washed with ether to give 3.01 (100%) of crude furo[3,2-b]pyridine-5,6-dicarboxylic acid anhydride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[C:5]([O:11][CH2:12][CH3:13])=[CH:4][C:3]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.Cl.[NH2:23][CH2:24][C:25]([O:27]CC)=O>>[CH2:14]([CH:24]1[N:23]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]2[CH:4]=[C:5]([O:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[CH:7][C:2]=2[NH:1][C:25]1=[O:27])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCOc1cc(N)c(C(=O)c2ccccc2)cc1OCC
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOc1cc2c(cc1OCC)C(c1ccccc1)=NC(Cc1ccccc1)C(=O)N2
Yield: 19 %

Procedure:
By replacing (2-amino-4,5-dimethoxyphenyl)(phenyl) methanone (XXIaa) in example XXIIaa by (2-amino-4,5-diethoxyphenyl)(phenyl)methanone (XXIag), and ethyl glycinate hydrochloride by methyl phenylanalilate hydrochloride, and proceeding in the same manner, the abovenamed product is obtained. Yield: 19%. M: 10–112° C. 1H-NMR (CDCl3, 200 MHz): d 1.38 (t, 3H, CH3), 1.55 (t, 3H, CH3), 3.61–3.66 (m, 2H, CH2), 3.82–3.98 (m, 3H, CH+OCH2), 4.18 (q, 2H, OCH2), 6.64 (s, 1H Ar), 6,75 (s, 1H Ar), 7.25–7.57 (m, 10H Ar), 8.65 (s, 1H exchangeable, —NH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[C:11]([NH:13][C:14]([NH:17][CH3:18])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: NCCSCc1nccs1
Reactant: CN=C(NC#N)SC
Product: CNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of [(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide 20.2 g.) with N-cyano-N',S-dimethyl-isothiourea (7.75 g.) by a procedure similar to that described in Example 3(a) afforded N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine, m.p. 120°-122.5° , following chromatography on silica gel with acetonitrile as eluant, and recrystallisation from isopropyl alcohol. (Found: C, 42.3; H, 5.1; N, 27.2, S, 23.3. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(Cl)cc2)c(C)[nH]1
Yield: 83 %

Procedure:
4-[2-(4-Chlorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (108) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-chlorophenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/RT. Purification: recrystallization from ether/pentane. Yield: 83%. 1H (CDCl3, 400 MHz): δ 9.65 (NH, broad s), 7.28 (3H, m), 7.2 (2H, d), 4.35 (2H, q), 4.04 (2H, s), 2.57 (3H, s), 1.38 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 193.7, 161.5, 141.0, 133.5, 132.6, 130.9, 130.7, 128.9, 128.6, 121.4, 120.5, 116.9, 61.0, 46.1, 14.4, 14.0 ppm. LC/MS: 100%
Reaction SMILES: [CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([OH:29])=O)=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC=CC=1C.[NH:68]1[CH2:73][CH2:72][S:71](=[O:75])(=[O:74])[CH2:70][CH2:69]1>C(Cl)Cl.CN(C=O)C>[CH:1]1([N:4]([CH:33]2[CH2:35][CH2:34]2)[C:5]([C:7]2[N:30]([CH2:31][CH3:32])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][C:22]([C:27]([N:68]5[CH2:73][CH2:72][S:71](=[O:75])(=[O:74])[CH2:70][CH2:69]5)=[O:29])=[C:23]([CH2:25][CH3:26])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)O
Reactant: O=S1(=O)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCc1nc(Nc2nc3c(cc(C(=O)N(C4CC4)C4CC4)n3CC)c3c2ncn3C)sc1C(=O)N1CCS(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 53 %

Procedure:
To a stirred solution of 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylthiazole-5-carboxylic acid (example 69B, 33 mg, 0.067 mmol), HATU (50.8 mg, 0.134 mmol), 2,6-lutidine (0.020 mL, 0.174 mmol), and DMF (1 mL) was added thiomorpholine 1,1-dioxide (27.1 mg, 0.201 mmol). The solution was then stirred at 50° C. for 1.5 hrs. The reaction was then cooled to room temperature and diluted with methylene chloride. The solution was then washed with saturated aqueous sodium bicarbonate, 10% LiCl in H2O, and saturated aqueous sodium bicarbonate again. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude residue was then purified by silica-gel flash chromatography using an Isco 40 g column eluting from 0-6% MeOH/CH2Cl2 to give N,N-dicyclopropyl-6-ethyl-4-(4-ethyl-5-(1,1-dioxothiomorpholine-4-carbonyl)thiazol-2-ylamino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (21.7 mg, 52.6% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[CH2:13][N:14]([CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].ClC1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][N:14]([CH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[O:2][C:1]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19]
Reactant: COc1cccc2c(CN(CCC(C)C)CCC(C)C)cccc12
Reactant: N#Cc1ccc(Cl)nc1
Product: CC(C)CCN(CCC(C)C)Cc1cccc2c(Oc3ccc(C#N)cn3)cccc12

Procedure:
Using the procedure outlined in Preparation 14 and Preparation 15, (5-methoxynaphthalen-1-ylmethyl)-bis-(3-methylbutyl)amine (Preparation 29) and 2-chloro-5-cyanopyridine were converted to the title compound: RT=2.93 min; m/z (ES+)=416.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2(O)[C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1.O=S(Cl)[Cl:25]>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:9](=[O:10])[O:8][C:7]2([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)[Cl:25]
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(Cl)cccc32)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)nc(C2(Cl)OC(=O)c3c(Cl)cccc32)n1

Procedure:
A mixture of 0.7 g of 7-chloro-3-hydroxy-3-(4,6-dimethoxy-2-pyrimidinyl)phthalide, 30 ml of CCl4, 2 ml of SOCl2 and 4 drops of DMF are refluxed at 60° for 11/2 hrs. The mixture is then cooled, excess SOCl2 and CCl4 removed on a rotovaporator. The residue is diluted with 20 ml of CH2Cl2 and added to a stirred mixture of 10 ml of methanol and 2 ml of diethylamine. After 21/2 hrs the mixture is stripped on a rotovaporator to remove excess CH2Cl2 and methanol and the residue partitioned between CH2Cl2 (50 ml) and water (50 ml). The organic phase is separated, concentrated and the gummy residue flash chromatographed over silica gel using 80/20 hexane/ethyl acetate (500 ml), 60/40 hexane/ethyl acetate (500 ml) (28 fractions×50 ml). Fractions 18 to 20 yielded title compound a) and fractions 11 to 16 the compound b).