Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.P(Cl)(Cl)([Cl:25])=O>COCCOC>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:25])=[N:7][C:8]([CH2:12][Cl:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(CCl)nc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: COCCOC
Product: ClCc1nc(Cl)c2ccc(Br)cc2n1
Temperature: 25 °C

Procedure:
Heat a mixture of 7-bromo-2-chloromethyl-3H-quinazolin-4-one (5 g, 18.2 mmol), 2,6-lutidine (5 g), and phosphorus oxychloride (5 mL) in 1,2-dimethoxyethane (500 mL) at 80° C. for 16 hours. Cool the mixture to room temperature and fully evaporate the mixture, then dilute with ether and wash with water. Dry the solvent (Na2SO4) and evaporate the ether to obtain 7-bromo-4-chloro-2-chloromethylquinazoline (3.5 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][N:6]=1)=[O:4].[OH-].[Na+].C1COCC1>O>[N:11]1([C:8]2[N:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1cnc(N2CCCCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(N2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
5-Piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester (Preparation 42, 85.1 g, 384 mmol) was added to a solution of sodium hydroxide (61.5 g, 1.53 mol) in water (760 mL). The mixture was stirred mechanically for 1 hour at room temperature. THF (300 mL) was added and stirring was continued for 3 hours. The volatile solvents were removed in vacuo and the remaining aqueous solution was adjusted to pH 4. The mixture was cooled on ice to induce precipitation of the product. The resulting solid was collected by filtration and dried in vacuo to give the title compound as a white solid (56 g) in a 70% yield.
Reaction SMILES: C([O:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]2[O:37][N:36]=[C:35]([C:38]([O:40]CC)=[O:39])[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1)(=O)C1C=CC=CC=1.O.O.[OH-].[Li+]>O1CCOCC1.Cl>[OH:9][CH2:10][C@:11]12[CH2:46][CH2:45][C@@H:44]([C:47]([CH3:49])=[CH2:48])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:43])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20]([C:33]2[O:37][N:36]=[C:35]([C:38]([OH:40])=[O:39])[CH:34]=2)=[CH:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)OCC)no6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cc(C(=O)O)no6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 32590.9 %

Procedure:
To a solution of ethyl 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(benzoyloxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)isoxazole-3-carboxylate (0.015 g, 0.022 mmol) in 1,4-Dioxane (2 mL) was added Water (0.5 mL) and Lithium hydroxide monohydrate (0.17 g, 4.05 mmol). The mixture was heated to 75° C. After 3.5 h the mixture was cooled to rt and was diluted with 1N HCl (7 mL) then was extracted with dichloromethane (4×7 mL). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by crystallization using dioxane, water, and methanol. The expected product, 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)isoxazole-3-carboxylic acid (4 mg, 7.17 mmol, 31.9% yield), was isolated as a white solid. LCMS: m/e 536.35 (M+H)+, 2.03 min (method 7). 1H NMR (500 MHz, Pyr) δ ppm 0.87 (s, 3H), 0.96-1.88 (m, 20H), 1.04 (s, 3H), 1.05 (s, 3H), 1.17 (s, 3H), 1.21 (s, 3H), 1.81 (s, 3H), 2.14-2.27 (m, 1H), 2.39-2.53 (m, 1H), 2.59-2.74 (m, 1H), 3.70 (d, J=10.99 Hz, 1H), 4.12 (d, J=10.99 Hz, 1H), 4.80 (br. s., 1H), 4.94 (s, 1H), 6.40 (d, J=6.41 Hz, 1H), 7.08 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:20]2[C:15](=[N:16][C:17]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](S(C)(=O)=O)[N:22]=3)[CH:19]=2)[NH:14][N:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:41]1([CH2:44][NH2:45])[CH2:43][CH2:42]1>>[CH:41]1([CH2:44][NH:45][C:23]2[N:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])=[N:13][NH:14][C:15]4=[N:16][C:17]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:26]=[CH:25][N:24]=2)[CH2:43][CH2:42]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1nccc(-c2cc3c(NC(=O)OCc4ccccc4)n[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Product: O=C(Nc1n[nH]c2nc(-c3cccc(C(F)(F)F)c3)c(-c3ccnc(NCC4CC4)n3)cc12)OCc1ccccc1

Procedure:
Following a similar procedure to that described in example 208, but starting from N-benzyloxycarbonyl-[5-(2-methylsulfonylpyrimidin-4-yl)-6-(3-trifluoromethylphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]amine (obtained in section b) and (cyclopropylmethyl)amine, the desired compound was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)C=C.[CH3:25][C:26]1C=CC=C[C:31]=1C>>[CH2:31]([C:6]1[C:5]([OH:4])=[C:14]([O:15][CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[N:9][CH:10]=[N:11]2)[CH:26]=[CH2:25]
Reactant: C=CCOc1cc2c(Nc3ccc(Cl)cc3)ncnc2cc1OC
Reactant: Cc1ccccc1C
Product: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12

Procedure:
A solution of (6-allyloxy-7-methoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine (0.50 g, 1.46 mmol) (from Example 16, Step C, supra) in o-xylene (50 mL) was heated at 150° C. for 7 hours. At the end of this period, TLC analysis indicated almost complete consumption of the starting material and the formation of desired product as the major spot. The solvent was evaporated and the residue was purified by chromatography using EtOAc/Et3N (1:0.04) as eluent to give the desired 5-allyl-4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol as an off white solid. (Yield 0.4 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH2:6][CH:7]([CH3:26])[N:8]([C:20](=[O:25])[C:21](F)(F)F)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[C:29](OC(=O)CC)(=O)CC>>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[CH2:6][CH:7]([CH3:26])[N:8]([C:20](=[O:25])[CH2:21][CH3:29])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: CCC(=O)OC(=O)CC
Reactant: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=O)C(F)(F)F
Product: CCC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Br)ccc2CC1C
Yield: 70 %

Procedure:
1.33 g (3.7 mmoles) of 8-bromo-4-methyl-1-(4-nitrophenyl)-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 22, Step D) are acylated with propionic anhydride using the method of Example 1. The crude product is purified by chromatography over a silicagel column that is eluted with a mixture of hexane and ethyl acetate in a ratio of 9:1. Thus, 1.07 g (70%) of the title compound are obtained. M.p.: 178°-180° C.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1>C(OCC)C>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[NH:5][S:2]([Cl:1])(=[O:4])=[O:3])=[CH:10][CH:11]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: Cc1ccc(NC(=O)NS(=O)(=O)Cl)cc1
Temperature: -40 °C
Yield: 80 %

Procedure:
This compound was prepared according to J. Med. Chem. 1996, 39, 1243-1252. Briefly, a solution of chlorosulfonylisocyanate (1.62 g, 11.5 mmol, 1 eq.) was diluted in dry diethylether and the resulting solution was cooled at −50° C.<T<−40° C. To this solution, p-toluidine (1.23 g, 11.5 mmol, 1 eq.) was added. The solution was stirred at −35° C. for 10′ and a suspension was obtained. The solid was filtered and washed with diethyl ether. Yield 80%, 2.3 g.
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:20]1[N:15]([CH2:14][CH2:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1

Procedure:
1.08 gram of DTPA (2.7 mmol), 2 mL acetic anhydride and 1.3 mL pyridine were stirred for 48 hours at 60° C. and then the reaction mixture was filtered at room temperature. The solid product washed to be free of pyridine with acetic anhydride and then with diethyl ether, and is dried.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([O:15][CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)CBr
Reactant: OC1(c2ccc(Br)cc2)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ambient suspension of NaH (332 mg, 8.30 mmol, 60 wgt % in mineral oil) in N,N-dimethylformamide (2 mL) was added dropwise a solution of Example 30A (1.0 g, 4.15 mmol) in N,N-dimethylformamide (1 mL). After 30 min., bromoacetic acid (577 mg, 4.15 mmol) in N,N-dimethylformamide (13 mL) was added dropwise. The solution was stirred at room temperature for 16 h and then heated to 50° C. for 3 h. The reaction was cooled to room temperature and was quenched by the addition of water (10 mL). The solution was basicified to pH 10 by the addition of 2.5 M NaOH. The aqueous was extracted with ethyl acetate (2×10 mL), and the organics discarded. The aqueous was acidified to pH 1 with 6 M HCl, and then extracted with ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated, under reduced pressure to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.66-1.72 (m, 2H), 1.74-1.85 (m, 4H), 2.02-2.15 (m, 2H), 3.56-3.60 (m, 2H), 7.33-7.39 (m, 2H), 7.49-7.56 (m, 2H), 12.37 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([O:17]C)=O)=[CH:5][C:4]=2[NH:3]1.[OH-].[Na+].[NH3:21]>>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]([NH2:21])=[O:17])=[CH:5][C:4]=2[NH:3]1
Reactant: N
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc2c(c1)[nH]c(=O)c1ccsc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
In a closed vessel, Methyl 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (44 mg, 0.170 mmol) was suspended in concentrated aqueous ammonia (1 ml). The mixture was stirred at 100° C. overnight. Aqueous 1N NaOH was added and the mixture stirred at room temperature for 2 hours. The solid was filtered and dried to provide 4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxamide as a brown solid (13 mg, 32% yield). LCMS (ES): 95% pure, m/z 245 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)CC)C>ClCCl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)ccc1C1(NC(=O)C2CC2)C(=O)c2ccccc2C1=O
Yield: 103.8 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with cyclopropyl carbonyl chloride (0.07 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (235 mg, 96%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([C:33]([N:35]2[CH2:38][CH2:37][CH2:36]2)=[O:34])[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:35]1([C:33]([CH:31]2[CH2:32][N:29]([CH2:11][C:10]3[N:2]([CH3:1])[C:3]4[C:8]([N:9]=3)=[C:7]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:6]=[C:5]([N:19]3[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[C:20]3[CH3:28])[N:4]=4)[CH2:30]2)=[O:34])[CH2:38][CH2:37][CH2:36]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C(C1CNC1)N1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(C(=O)N4CCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and azetidin-3-ylazetidin-1-ylmethanone (45 mg, 0.31 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 90:10 to 85:15) to afford 347 as a white solid (30 mg, 23%). LCMS (Method G): RT=5.33 min, M+H+=502. 1H NMR (CDCl3, 400 MHz) δ 8.07 (m, 1 H); 7.69 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 4 H); 4.13-4.00 (m, 4 H); 3.87 (m, 6 H); 3.82 (s, 3 H); 3.68-3.58 (m, 2 H); 3.53-3.45 (m, 2 H); 3.34-3.26 (m, 1 H); 2.96 (s, 3 H) and 2.33-2.23 (m, 2 H)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:30]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[F:37][CH:38]([F:62])[O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][N:44]=[C:43]2[Sn](CCCC)(CCCC)CCCC>CN(C=O)C.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.[Cu]I>[C:33]([NH:32][C:30]([C:8]1[C:6]2=[N:7][C:2]([C:43]3[C:42]4[C:46](=[CH:47][CH:48]=[C:40]([O:39][CH:38]([F:37])[F:62])[CH:41]=4)[NH:45][N:44]=3)=[CH:3][N:4]=[C:5]2[N:10]([C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:9]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
In a round-bottomed flask, 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (530 mg, 1 mmol) and 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (470 mg, 1 mmol) were dissolved in DMF (10 mL) under nitrogen. Pd(PPh3)4 (58 mg, 0.05 mmol) and CuI (38 mg, 0.2 mmol) were added and mixture sonicated for 5 min while bubbling nitrogen. The reaction mixture was stirred at 80° C. for 4 hours. The concentrated mixture was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (3:1 to 1:1, v/v) to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (410 mg, 64%) as a solid. MS: (M+H)+=643.2; 1H NMR (300 MHz, CDCl3): δ 8.85 (d, 1H, J=2.4 Hz), 8.35 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H,), 7.52-7.48 (m, 1H), 6.51 (t, 1H, J=74.0 Hz), 1.60 (s, 9H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:31]([O-])([N+]([O-])=O)=[O:32]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:31]=[O:32])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 77.7 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-n-hexyl-3-D-glucopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 3.1 g of 1-(2-chloroethyl)-1-nitroso-3-n-hexyl-3-D-glucopyranosylurea are thereby obtained as a yellow oil.
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.[C:12](Cl)(=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH2:14][CH2:13][C:12]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (825 mg, 5.46 mmol) in anydrous pyridine (16 mL) was added dropwise hydrocinnamoyl chloride (990 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 1200 mg) was added and the resulting mixture was stirred overnight at rt. After rinsing the resin and filtration, water (200 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1.40 g) was obtained as a white solid (90%) in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:32])[C:3]=1[OH:33].O[C@@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36]([O:38]C)=[O:37]>>[Br:32][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([S:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:33][C@H:35]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:36]([OH:38])=[O:37]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Sc3ccncc3)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Sc3ccncc3)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-[6-(pyridin-4-ylsulfanyl)-benzo [b]naphtho[2,3-d]thiophen-11-yl]-phenol (Example 65) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO- d6); δ13.3 (broad singlet, 1 H), 8:45 (m, 2 H), 8.37 (d, J=8 Hz, 1 H), 7.99 (d, J=8 Hz, 1 H), 7.85 (dd, J=7, 2 Hz, 2 H), 7.77-7.74 (m, 1 H), 7.66-7.65 (m, 2 H), 7.50 (t, J 7 Hz, 1 H), 7.43-7.25 (m, 8H), 6.68 (d, J=8 Hz, 1 H), 5.35 (dd, J 8 ,2 Hz, 1 H), 3.43 (d, J=7 Hz, 2 H); MS [+FAB]: [(M+H)+], 739.9 (70%), 741.9 (100%), 743.9 (90%); MS High resolution (FAB)+ve, calc mass for C36H24Br2NO3S2 739.95644; measured mass 739.96224, mass deviation 5.80 mmu. Anal. Calc. for C36H23Br2NO3S2: C, 55.58, H, 3.11, N, 1.80. Found: C, 55.38, H, 3.37, N, 1.92.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[N:14]2[C:10]([S:11][CH:12]=[CH:13]2)=[N:9][C:8]=1[CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[H-].[Na+].[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2[CH:44]=O)[CH2:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[CH:37]1([CH2:40][O:41][C:42]2[C:49]([O:50][CH3:51])=[CH:48][CH:47]=[CH:46][C:43]=2/[CH:44]=[CH:15]/[C:8]2[N:9]=[C:10]3[N:14]([C:7]=2[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:13]=[CH:12][S:11]3)[CH2:38][CH2:39]1
Reactant: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2sccn12
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC)c2OCC2CC2)nc2sccn12
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Step 3 intermediate (2.0 g, 3.626 mmol) was added NaH (0.160 g, 3.989 mmol) in anhydrous DMSO (10 mL) and stirred for 30 min. A solution of 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (0.82 g, 3.989 mmol) in anhydrous DMSO (10 mL) was added drop wise to this solution at room temperature and stirred for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), brine and dried (Na2SO4) to yield a crude solid which was purified by column chromatography using 5% ethyl acetate in petroleum ether to afford 0.776 g of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.50-0.53 (m, 2H), 1.17-1.23 (m, 1H), 1.39 (t, J=7.5 Hz, 3H), 3.75 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.37 (q, J=6.9 Hz, 2H), 6.95-6.99 (m, 2H), 7.08 (t, J=7.8 Hz, 1H), 7.18-7.22 (m, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.69 (d, J=16.2 Hz, 1H), 7.92 (d, J=16.5 Hz, 1H), 8.10 (d, J=4.2 Hz, 1H); ESI-MS (m/z) 399.20 (MH)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C33H40Cl2N5O2 [(M+H)+] 608.2554, observed 608.2554.