Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22]O)[CH2:17]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH:18]3[CH2:19][CH2:20][CH2:21][N:16]([CH3:15])[CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCCC(CO)C1
Reactant: COc1cc2c(N)ncnc2cc1O
Product: COc1cc2c(N)ncnc2cc1OCC1CCCN(C)C1

Procedure:
4-Amino-6-methoxy-7-(N-methylpiperidin-3-ylmethoxy)quinazoline was prepared by reaction of 4-amino-6-methoxy-7-hydroxyquinazoline with 1-methyl-3-piperidinemethanol under analogous conditions to those described Example 2, Note[11]:—Mass Spectrum: M+H+ 303.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([F:15])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Cl:14][C:11]1[C:10]([F:15])=[C:9]2[C:8]([CH2:7][CH2:6][NH:5][C:4]2=[O:3])=[CH:13][CH:12]=1
Reactant: CCOC(=O)NCCc1ccc(Cl)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2ccc(Cl)c(F)c21
Yield: 14.2 %

Procedure:
Using the same reaction procedure and workup as described in example 1, [2-(4-chloro-3-fluoro-phenyl)-ethyl]-carbamic acid ethyl ester (I-33c: 1.3 g, 5.30 mmol) in POCl3 (10 mL) was reacted with P2O5 (1.5 g, 10.60 mmol) at 110° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 150 mg of the product (14% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18](O)=[O:19])[O:14][C:13]=2[CH:21]=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH:16]=[C:15]([C:18]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:19])[O:14][C:13]=2[CH:21]=1
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C1=COc2ccc(O)cc2O1
Yield: 63 %

Procedure:
That compound is obtained in a yield of 63% starting from aniline and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[N:10]=2)[S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])=[CH:6][CH:7]=1
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cn1c(N(c2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)nc2ccccc21
Temperature: 100 °C

Procedure:
To (4-chloro-phenyl)-(1-methyl-1H-benzimidazol-2-yl)-amine (258 mg, 1.0 mmol) in anhydrous pyridine (4 mL) at room temperature was added benzenesulfonyl chloride (706.5 mg, 4.0 mmol). The resulting mixture was heated to 100° C. in a microwave reactor for 1 h. The resulting mixture was then diluted with EtOAc, washed with 1 N HCl and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield the title compound as a crude residue, which was dissolved in ether containing 2.0M hydrogen chloride, and then concentrated in vacuo to yield the title compound as its corresponding HCl salt. MS 398 (M+1)+
Reaction SMILES: [CH3:1]C(C)[O-].[Na+].[Na].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]#[N:24])[NH:11][C:12]=1[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(OC)(OC)(=O)=O>C(O)(C)C>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:22][C:23]#[N:24])[N:11]([CH3:1])[C:12]=1[C:13](=[O:21])[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: N#CCc1cc(Cl)c(C(=O)c2ccc(Cl)cc2)[nH]1
Reactant: CC(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: Cn1c(CC#N)cc(Cl)c1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
To a refluxing solution of sodium isopropoxide in isopropanol (prepared by refluxing 0.69 g. (0.030 mole) of sodium in 70 ml. of isopropanol) is added 7.0 g. (0.025 mole) of 4-chloro-5-(p-chlorobenzoyl)-pyrrole- 2-acetonitrile prepared according to Example VIII, after which a solution of 3.78 g. (0.030 mole) of dimethyl sulfate in 10 ml. of isopropanol is added dropwise. When addition of the dimethyl sulfate solution is complete, the whole is refluxed for a half-hour and then poured into 1 liter of ice water. Filtration of the resulting mixture yields a grey solid, which is washed well with water and is then chromatographed with benzene on alumina. The chromatographed material is finally recrystallized from isopropanol to yield 4-chloro-5-(p-chlorobenzoyl)-1-methyl- pyrrole-2-acetonitrile as a beige solid; m.p. 139°-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2Br)=[O:8])[CH3:2].[CH3:24][Sn](C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:22])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[CH3:24])=[O:8])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(Br)c2sc1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(C)c2sc1=O
Temperature: 120 °C
Yield: 94.5 %

Procedure:
[(8-Bromo-6-chloro-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (500 mg, 1.19 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). Tetramethyl tin (247 μL, 1.783 mmol), dichloro(bis-triphenylphosphino) palladium (125 mg, 0.18 mmol), and 4 angstrom molecular sieves were added sequentially to the reaction. The reaction was sealed and heated to 120° C. in an oil bath for 45 min. The reaction was cooled, diluted with ethyl acetate, and partitioned with water. The organic phase was washed with water, brine, and dried over sodium sulfate. The crude material was purified by silica gel chromatography (15%-45% ethyl acetate in hexanes) to provide [(6-chloro-4-hydroxy-8-methyl-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (400 mg, 95%). MS ESI(−) m/e: 354.223 (M−1).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[C:16]3[N:18]([CH:21]4[CH2:26][CH2:25]C(=O)[CH2:23][CH2:22]4)[N:19]=[CH:20][C:15]3=[C:14]([N:28]3[CH2:34][CH:33]4[O:35][CH:30]([CH2:31][CH2:32]4)[CH2:29]3)[N:13]=2)=[CH:8][CH:7]=1)=[O:4].CO[CH:38]([O:41][CH3:42])[O:39][CH3:40].CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:42][O:41][C:38]1([O:39][CH3:40])[CH2:25][CH2:26][CH:21]([N:18]2[C:16]3=[N:17][C:12]([C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:11][CH:10]=4)=[N:13][C:14]([N:28]4[CH2:34][CH:33]5[O:35][CH:30]([CH2:31][CH2:32]5)[CH2:29]4)=[C:15]3[CH:20]=[N:19]2)[CH2:22][CH2:23]1
Reactant: COC(OC)OC
Reactant: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(=O)CC4)c3n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCC(OC)(OC)CC4)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (80 mg) (0.17 mmol) in DCM (2.0 mL) was added trimethylorthoformate and methanol in excess and a catalytic amount of p-toluene sulfonic acid along with molecular sieves and stirred at room temperature overnight. The added water and extracted 3 times with EtOAc. The organics were dried (MgSO4) and filtered off through a pad of Magnesol and concentrated in vacuo. to afford a solid. The solid was triturated with diethyl ether to give a white solid that was filtered and washed with diethyl ether to give (54 mg) MS m/z=476.2 (M+H).
Reaction SMILES: Cl.[NH2:2][OH:3].O(C(C)(C)C)[K].[Br:10][C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1>CS(C)=O.O>[Br:10][C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[NH:23])[NH:2][OH:3])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(-c2ccc(Br)o2)cc1
Reactant: NO
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: N=C(NO)c1ccc(-c2ccc(Br)o2)cc1
Reaction time: 0.5 h

Procedure:
To a chilled suspension of hydroxylamine hydrochloride (17.25 g, 0.25 mol) in DMSO (150 ml) was added portionwise KO-t-Bu (28.0 g, 0.25 mol) and the mixture was stirred under nitrogen for 30 min. 2-Bromo-5-(4-cyanophenyl)furan (17.37 g, 0.07 mol) was then added and the mixture was stirred overnight at room-temperature. The resulting solution was diluted with excess water to give 2-bromo-5-[4-(N-hydroxyamidino)phenyl]furan as an off-white solid, which was collected and washed with water. Yield: 19.45 g, 99%; mp 162-164° C. 1H NMR (DMSO-d6): 5.84 (broad s, 2H), 6.71 (d, J=3.6 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 9.70 (s, 1H). IR (cm−1): 3475, 3369, 3209 (broad), 1639, 1482, 1341, 1017, 927, 787. The intermediate amidoxime (38.9 g, 0.138 mol) was dissolved in a mixture of DMSO (60 ml) and dioxane (300 ml) and with chilling was treated with a solution of LiOH hydrate (11.61 g, 0.277 mol) in water (60 ml). At room temperature, the resulting suspension was then treated dropwise via an addition funnel with dimethyl sulfate (26.18 g. 0.208 mol) over the course of ˜30 min. Following the addition, the mixture became slightly warm and the solids dissolved. After stirring overnight, the mixture was diluted with excess water and extracted with EtOAc. Purification of the residue by column chromatography on silica gel eluting with 10% EtOAc in hexane gave the slightly impure product, which was further purified by recrystallization from MeOH/water in multiple crops to give an off-white solid, mp 116-117° C. Yield: 28.0 g, 69%. 1H NMR (DMSO-d6, an apparent mixture of stereoisomers): 3.74 (2s, 3H), 6.09 (broad s, 2H), 6.72 (2d, J=3.6 Hz, 1H), 7.09 (2d, J=3.6 Hz, 1H), 7.70 (m, 4H). IR (cm−1): 3459, 3312, 3177, 2957, 2935, 2901, 2818, 1634, 1403, 1051, 910, 842, 785.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.[CH:16]1([CH2:20][OH:21])[CH2:19][CH2:18][CH2:17]1>C1C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([O:21][CH2:20][CH:16]2[CH2:19][CH2:18][CH2:17]2)[C:3]([O:2][CH3:1])=[O:15])=[CH:7][CH:8]=1
Reactant: OCC1CCC1
Reactant: COC(=O)C(Cc1ccc(Cl)cc1)=[N+]=[N-]
Solvent: c1ccccc1
Product: COC(=O)C(Cc1ccc(Cl)cc1)OCC1CCC1
Temperature: 90 °C

Procedure:
To a solution of 500 mg (2.23 mmol) of methyl-2-diazo-3-(4-chlorophenyl)propanoate (obtained from Step A) and 1.05 mL (5 eq; 11.1 mmol) of cyclobutanemethanol in 5 mL benzene in a pressure tube was added 10 mg (1 mole %) of Rh2(OAc)4 catalyst. The tube was sealed and heated to 90° C. for 1.5 h. The solvents were evaporated under reduced pressure and the crude material was taken up in CH2Cl2 and purified by flash chromatography via gradient elution using mixtures of hexane and EtOAc (100:1 to 50:1). This provided the title compound as a clear oil. TLC Rf=0.53 (4:1 hexanes:EtOAc). 500 MHz 1H NMR (CDCl3): δ 1.68 (m, 2H); 1.85 (m, 1H); 1.88 (m, 1H); 2.01 (m, 2H); 2.53 (sep, 1H); 2.98 (m, 2H); 3.24 (dd, 1H); 3.58 (dd, 1H); 3.76 (s, 3H); 3.98 (dd, 1H); 7.20 (d, 2H); 7.28 (d, 2H).
Reaction SMILES: C([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([C:11]2[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5]1)C=C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][C:7]1([C:11]2[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:8]2[CH:6]1[CH2:5][NH:4][CH2:9]2
Reactant: C=CCN1CC2C(C1)C2(C)c1cccc(NS(C)(=O)=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Temperature: 35 °C

Procedure:
A stirred mixture of N-[3-(3-allyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Example 56, 1.90 g, 6.19 mmol), tetrakis(triphenylphosphine)palladium (0) (71.8 mg, 62.1 μmol) and N,N-dimethylbarbituric acid (2.91 g, 18.6 mmol) in dichloromethane (15 ml) was degassed and then heated to 35° C. under nitrogen for 3 h. The solution was rapidly stirred with aqueous hydrochloric acid solution (2M, 40 ml) and the aqueous portion was separated, this process was repeated. The combined aqueous layers were washed with dichloromethane (7×50 ml), and then concentrated in vacuo to give the hydrochloride salt of the title compound as an off white solid (1.40 g, 74%).
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].S(=O)(=O)(O)O>O>[CH2:11]1[O:12][C@@H:5]2[C@@H:3]([OH:4])[CH2:2][O:8][C@@H:7]2[C@@H:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O

Procedure:
Weighed amounts of aqueous 70% sorbitol solution were added to 12 separate glass reaction tubes. Each of these reaction tubes was connected to a water trap and set up according to the diagram in FIG. 1. The water trap contained 25 mL of water. Into each reaction tube was injected 483 μL of an aqueous solution containing 0.1075 g of concentrated sulfuric acid. The nitrogen purge into each tube was adjusted to 150 cm3/min. All of the reaction tubes were lowered at once into a 180° C. oil bath. Each tube was pulled from the oil bath at different times as listed in Table 1 to cool and stop the reaction. The mass of the crude remaining in each tube was determined. Small weighed samples of crude material (on the order of 150 mg) from each separate reaction tube were removed and diluted with a weighed amount of 1,9-nonanediol (external standard) contained in approximately 10 mL of anhydrous dimethylacetamide. Approximately 1 mL of each of these solutions was transferred to a gc vial, and treated with 0.150 ml of the silating agent trimethylsilylimidazole in order to determine and quantitate the components in each reaction tube by gas chromatographic analysis. The results of these experiments are presented in Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][C:12]([CH3:20])([CH2:16][C:17](O)=[O:18])[C:13](O)=[O:14]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:17](=[O:18])[CH2:16][C:12]([CH3:20])([CH3:11])[C:13]2=[O:14])[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Product: CC1(C)CC(=O)N(c2cccc([N+](=O)[O-])c2)C1=O

Procedure:
Sixty-nine grams (0.5 mole) of m-nitroaniline and 76 grams (g.) (0.52 mole) of 2,2-dimethylsuccinic acid were mixed with 200 milliliters (ml.) of xylene and heated to reflux until approximately 20 ml. of water was removed in a modified Dean Stark apparatus. On cooling, the product crystallized from solution. The mixture was diluted with 300 ml. of ether, the solid filtered off, washed with an additional 100 ml. of ether and dried. Yield was 117.5 g. of a product having a melting point (m.p.) of 134°-134.5° C. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O:35]CC)=[O:34].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH:21]([CH2:30][OH:31])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC(CO)Cc4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NC(CO)Cc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(1-(4-chlorophenyl)-3-hydroxypropan-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.111 g, 0.204 mmol) in 3:1 THF/ethanol (2 ml) was added 1M sodium hydroxide (0.428 ml, 0.428 mmol), and the reaction was stirred overnight. It was concentrated and then taken up in water. It was then acidified with 1M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 87 mg of the title compound (82.6% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:22]>O1CCOCC1>[NH2:22][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: COc1cc(NC(=O)c2c(Cl)ncnc2Cl)cc(OC)c1
Reactant: N
Solvent: C1COCCO1
Product: COc1cc(NC(=O)c2c(N)ncnc2Cl)cc(OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4,6-Dichloro-N-(3,5-dimethoxyphenyl)pyrimidine-5-carboxamide (684 mg, 1.21 mmol) was dissolved in dioxane (5 ml) and cooled in an ice bath. Ammonia solution (0.86 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 6 h and overnight at room temperature. After dilution with ethyl acetate, this organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield an oil as a residue (575 mg, 66% purity, 100% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[CH:8][C:9]=1[CH3:10].I[CH:13]([CH3:15])[CH3:14]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([S:11][CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(S)cc1Br
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(SC(C)C)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of NaH (40 mg) in anhydrous DMF (5 mL) was treated with a solution of 3-bromo-4-methylbenzenethiol (200 mg) in anhydrous DMF (3 ml). The reaction mixture was stirred for 30 minutes at RT, then 2-iodo propane (0.14 ml) was added to the reaction mixture and the reaction mixture was heated to 55° C. for 3 hours. The reaction mixture was quenched with ice and extracted with diethylether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Silica gel), eluting with hexane, to give the title compounds.
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([Sn](C)(C)C)=[CH:12][N:13]=[C:8]2[NH:7][CH2:6][C:5]1=[O:18])([CH3:3])[CH3:2].Br[C:20]1[C:25]([CH3:26])=[CH:24][C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[C:22]([F:38])[CH:21]=1>CN(C)C=O.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>[F:38][C:22]1[C:23]([C:27]2[N:31]=[CH:30][N:29]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:28]=2)=[CH:24][C:25]([CH3:26])=[C:20]([C:11]2[N:10]=[C:9]3[N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:18])[CH2:6][NH:7][C:8]3=[N:13][CH:12]=2)[CH:21]=1
Reactant: CC(C)N1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Reactant: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ncn(C3CCCCO3)n2)c(F)cc1-c1cnc2c(n1)N(C(C)C)C(=O)CN2
Temperature: 140 °C
Yield: 52.7 %

Procedure:
1-Isopropyl-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (300 mg, 0.84 mmol), 3-(4-bromo-2-fluoro-5-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (428 mg, 1.26 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmol) were combined in N,N-dimethylformamide (5 mL). The mixture was degassed and heated at 140° C. under nitrogen for 3 h. After being cooled to room temperature, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by preparative TLC (15% methanol in dichloromethane) to give the title compound (200 mg, yield 52%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[C:22]2[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([OH:28])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:29][CH2:30][OH:31])[C:12]=2[CH:11]=1.[H][H]>[Pd]>[OH:28][C:17]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:29][CH2:30][OH:31])[C:12]3[CH:11]=[C:10]([C:3]4[CH:2]=[CH:7][CH:6]=[CH:5][C:4]=4[O:8][CH3:9])[C:22]4[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:21]=4[C:20]=3[C:19]=2[CH:18]=1
Reactant: [H][H]
Reactant: COc1cccc(Cl)c1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCO
Agent: [Pd]
Product: COc1ccccc1-c1cc2c(c3c1C(=O)NC3=O)c1cc(O)ccc1n2CCO
Yield: 77 %

Procedure:
Reaction of 4-(2-Chloro-6-methoxyphenyl)-9-hydroxy-6-(2-hydroxyethyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar-2-chloro-6-methoxyphenyl, R10═CH2CH,OH) (112) prepared as described in example 64 with hydrogen gas, using a Pd/C catalyst, according to the procedure for example 60 gave 9-Hydroxy-6-(2-hydroxyethyl)-4-(2-methoxyphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (VI; Ar=2-methoxyphenyl, R10═CH2CH2OH) (113) in a 77% yield as a yellow solid; mp 285–289° C. 1H NMR δ [(CD3)2SO] 10.91 (br s, 1H), 9.29 (br s, 1H), 8.37 (d, J=2.4 Hz, 1H), 7.70 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 7.42 (m, 1H), 7.33 (dd, J=8.8, 2.4 Hz, 1H), 7.12–7.02 (m, 3H), 4.84 (t, J=5.5 Hz, 1H), 4.73 (t, J=5.3 Hz, 2H), 3.76 (dt, J=5.5, 5.3 Hz, 2H), 3.68 (s, 3H). Found: C, 67.30; H, 4.47; N, 6.79. C23H18N2O5.1/2H2O requires C, 67.15; H, 4.65; N, 6.81.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24]C)[CH:21]=[C:20]([Cl:26])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19].B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:26][C:20]1[CH:21]=[C:22]([OH:24])[CH:23]=[C:2]([Cl:1])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: O=C1C(Cc2c(Cl)cc(O)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Temperature: 0 °C
Reaction time: 28 h
Yield: 74 %

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (Example 1) (15.0 g, 38 mmol) in methylene chloride (1.5 L) and cool to 0° C. Treat with boron tribromide (19.9 mL, 190 mmol) dropwise over 30 minutes and allow reaction mixture to warm to room temperature. Stir for 28 h at room temperature, re-cool in an ice-bath, add methanol (38 mL) carefully over 15 minutes to the stirred reaction mixture. Remove organic solvents by rotary evaporator, and dissolve the residue in 4:1 chloroform/isopropyl alcohol (600 mL) and water (100 mL). Neutralize to pH 7 using 5 N NaOH, separate, reserve the organics and extract the aqueous layer with two portions of chloroform/isopropyl alcohol. Dry the combined organics over sodium sulfate, filter and evaporate to a solid and vacuum dry at 90° C. to yield 10.7 g (75%) of the titled compound. MS (m/z): 380 (m+1).