Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([N:9]=[CH:10]N(C)C)=[C:4]([Cl:14])[N:3]=1.P([O-])([O-])([O-])=[O:16].[K+].[K+].[K+].OP([O-])(O)=O.[K+].P(=O)(O)(O)O>P(=O)(O)(O)O.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:10]=[O:16])=[C:4]([Cl:14])[N:3]=1
Reactant: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Reactant: O=P([O-])([O-])[O-]
Agent: O=P(O)(O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1nc(Cl)c(NC=O)c(Cl)n1
Temperature: 125 °C
Yield: 68 %

Procedure:
A slurry of 2-amino-4,6-dichloro-5-{[(dimethylamino)methylene]amino}pyrimidine (Example 2, 1.50 g, 6.41 mmol) and 1.5M aqueous potassium phosphate buffer (35 mL, prepared by adjusting the pH of a 1.5M solution of KH2PO4 to 3.2 by addition of 85% phosphoric acid) was gently refluxed (in an oil bath at 125° C.). After 4 hours of reflux, the pH of the mixture was adjusted from 4 to 3 by addition of 4 drops of 85% phosphoric acid. After a total of 6 hours of reflux, TLC(silica gel plates developed in 5% methanol-chloroform) showed that the starting material had been largely converted to a lower-Rf product. The solid was filtered and washed with water (5 mL), methanol (5 mL), and dried to give the title compound as a white solid (0.900 g, 68%), mp. >250° C. dec.; mass spectrum (CI/CH4): 209, 207 (M+1); 1H-NMR (DMSO-d6)δ: 9.81 and 9.46 (s and d, J=11 Hz, total 1, NH), 8.25 and 8.00 (s and d, J =11 Hz, total 1, CHO), 7.69 and 7.63 (both s, total 2, NH2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[S:13])[NH2:12])=[CH:7][CH:6]=1)[CH3:2].Br[CH2:16][C:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=O.Br>C(O)(C)C.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:13][CH:16]=[C:17]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(CBr)c1cccnc1
Reactant: CCOC(=O)c1ccc(C(N)=S)cc1
Agent: Br
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2nc(-c3cccnc3)cs2)cc1

Procedure:
4-Thiocarbamoyl-benzoic acid ethyl ester (CAS 78950-31-9) (0.4 g, 1.91 mmol), and 2-Bromo-1-pyridin-3-yl-ethanone; hydrobromide (CAS 17694-68-7) (0.537 g, 1.91 mmol) is placed in a 100 mL flask and dissolved in 20 mL of isopropyl alcohol. The mixture is heated to reflux for 1.5 hours and cooled and diluted with 40 mL of diethyl ether. The resulting solid is filtered and dissolved in a mixture of dichloromethane and saturated sodium bicarbonate solution. The organics are separated, dried over sodium sulfate, filtered and concentrated to provide 0.565 g of the titled compound. MS (m/e) 311.1 (M+1)
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22].C(O)CCC>O>[F:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Yield: 20.1 %

Procedure:
A solution of 20.0 g of 1-acetyl-4-(2,4-difluorobenzoyl)-piperidine, 60 ml of hydrazine hydrate and 150 ml of n-butanol was refluxed for 48 hrs. The reaction was poured into 11 of water, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. Recrystallization of the residue from isopropanol-water and then from isopropanol yielded 3.3 g (20.1%) of product, mp 214°-216° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[N:13]([CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29])[CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1
Reactant: COC(CCBr)OC
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCn1cc(-c2ccc(C)nc2Cl)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 5-(2-Chloro-6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep107, 345 mg, 1.27 mmol), K2CO3 (174 mg, 1.27 mmol) and 3-bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) in DMF (3 ml) was stirred at room temperature overnight. 3-Bromo-1,1dimethoxy-propane (86 μl, 0.63 mmol) was then added and the reaction mixture stirred for additional 2 days. Water was added and the aqueous layer washed with diethylether and then the product extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with ethyl acetate-NH4OH (100-0.25) to give 90 mg of the title compound (21% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10][C:9](=S)[C:8]=2[N:7]=1)=[O:5])[CH3:2].FC(F)(F)S(OC)(=O)=O.[CH3:30][O:31][CH2:32][CH2:33][C@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][NH:35]1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:15][C:14]2[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[N:10]=[C:9]([N:38]3[CH2:37][CH2:36][NH:35][C@@H:34]([CH2:33][CH2:32][O:31][CH3:30])[CH2:39]3)[C:8]=2[N:7]=1)=[O:5])[CH3:2]
Reactant: COCC[C@H]1CNCCN1
Reactant: CCOC(=O)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCOC)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 10-thioxo-9,10-dihydro-4H-3-thia-1,4,9-triaza-benzo[f]azulene-2-carboxylic acid ethyl ester (3.59 g, 11.76 mmol) in 25 mL CH2Cl2 and add methyl trifluoromethanesulfonate (2.41 g, 14.7 mmol) dropwise at 0° C., stir at 0° C. for half hour, and warm to RT. After 2 h, concentrate the reaction mixture under reduced pressure, mix with (S)-2-(2-methoxy-ethyl)-piperazine (0.1.47 g, 10.2 mmol) in 20 mL pyridine and heat to 100° C. After 4 hours, cool the reaction to RT, and concentrate to a residue. Purification by flash chromatography (twice) on silica gel using a gradient (100% CH2Cl2 to 100% mixed solvent of (CH2Cl2: 2N NH3/MeOH=20:1)) over 55 min. gives the title compound: mass spectrum (electrospray) (m/e): C20H25N5O3S, Calc. Mass (M+1): 416.1756, Found: 416.1748. 1H NMR (400 MHz, CDCl3): δ 7.05-6.98 (m, 2H), 6.91-6.85 (m, 1H), 6.65-6.62 (m, 1H), 5.51 (br, 1H), 4.40 (q, 2H, J=7.5 Hz). 4.10 (br, 2H), 3.51 (t, 2H, J=6.0 Hz), 3.32 (s, 3H), 3.30-3.00 (m, 4H), 2.79-2.72 (m, 1H), 1.79-1.66 (m, 2H), 1.38 (t, 3H, J=7.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O.[NH2:25][NH2:26]>CCO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:25][NH2:26])=[O:19])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
To a suspension of methyl 4-{[3-(3,4-dihydroxyphenyl)propanoyl]amino}benzoate (227 mg, 0.72 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.55 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave 117 mg of the title compound (52%) as a white solid in 99.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[Cl:8][C:9]1[CH:22]=[C:21]2[C:12]([N:13]([OH:33])[C:14]3[CH2:15][CH:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH2:17][C:18](=O)[C:19]=3[C:20]2=[O:23])=[CH:11][CH:10]=1>C(O)C>[Cl:8][C:9]1[CH:22]=[C:21]2[C:12]([N:13]([OH:33])[C:14]3[CH2:15][CH:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=4)[CH2:17][C:18](=[N:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[C:19]=3[C:20]2=[O:23])=[CH:11][CH:10]=1
Reactant: O=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Reactant: CN(C)CCCN
Solvent: CCO
Product: CN(C)CCCN=C1CC(c2ccc(Cl)c(Cl)c2)Cc2c1c(=O)c1cc(Cl)ccc1n2O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.4 g of N,N-dimethyl-1,3-propanediamine in 10 ml of ethanol is added dropwise to a stirred, cooled mixture of 4.1 g of 7-chloro-3-(3,4-dichlorophenyl)-3,4-dihydro-10-hydroxy-1,9(2H,10H)acridinedione in 100 ml of ethanol. The mixture is stirred at room temperature overnight and evaporated to dryness in vacuo. The residue is recrystallized from ethanol to give 7-chloro-3-(3,4-dichlorophenyl)1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro-10-hydroxy-9(2H)acridinone; mp 208°-210° C.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:31])([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[CH:33]([Sn](CCCC)(CCCC)CCCC)=[CH2:34]>O1CCOCC1>[F:1][C:2]1([F:32])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:31])([C:24]2[CH:29]=[CH:28][C:27]([CH:33]=[CH2:34])=[CH:26][CH:25]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:9])[CH2:3]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)[C@](O)(c2ccc(Br)cc2)[C@@H]2CCC(F)(F)C2)CC1
Solvent: C1COCCO1
Product: C=Cc1ccc([C@@](O)(C(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)[C@@H]2CCC(F)(F)C2)cc1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a solution of 125 mg of the t-butyl 4-((2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoyloxy)-tetrahydropyridine-1(2H)-carboxylate as obtained in Referential Example 52 in 4 ml of dioxane, 0.10 ml of vinyl tri-n-butyltin and 20 mg of tetrakistriphenylpalladium were added at room temperature, followed by 24 hours' heating under reflux at 110° C. in nitrogen atmosphere. Distilling the solvent off under reduced pressure, the resulting residue was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to provide 90 mg of the title compound.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[C:87]([O:91][C:92]([NH:94][C@H:95]1[CH2:99][CH2:98][N:97]([CH2:100][C:101]([OH:103])=O)[C:96]1=[O:104])=[O:93])([CH3:90])([CH3:89])[CH3:88]>>[C:87]([O:91][C:92]([NH:94][C@H:95]1[CH2:99][CH2:98][N:97]([CH2:100][C:101]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:103])[C:96]1=[O:104])=[O:93])([CH3:88])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(CC(=O)O)C1=O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)CN3CC[C@H](NC(=O)OC(C)(C)C)C3=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 34 %

Procedure:
The title compound was prepared in 34% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-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)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-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)benzoic acid, except (S)-2-(3-(tert-butoxycarbonylamino)-2-oxopyrrolidin-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 770.6 (M+H)+, 2.07 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83-6.60 (m, 1H), 5.29 (d, J=4.8 Hz, 1H), 4.76 (s, 1H), 4.63 (br. s., 1H), 4.32-4.16 (m, 1H), 4.07-3.84 (m, 2H), 3.44 (d, J=7.0 Hz, 2H), 2.70-2.56 (m, 2H), 2.55-2.44 (m, 1H), 2.43-2.31 (m, 1H), 2.13 (dd, J=6.3, 17.1 Hz, 1H), 2.08-1.95 (m, 1H), 1.94-1.82 (m, 2H), 1.81-1.73 (m, 2H), 1.71 (s, 3H), 1.68-1.62 (m, 1H), 1.61-1.48 (m, 6H), 1.46 (s, 9H), 1.43-1.22 (m, 6H), 1.13 (br. s., 1H), 1.10 (d, J=3.8 Hz, 3H), 1.02 (s, 6H), 0.95 (br. s., 3H), 0.94 (br. s., 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([C:27]([F:26])([F:35])[F:36])[CH:29]=1)=[O:7]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 83 %

Procedure:
To a solution of 3-bromo-4-methylbenzoic acid (1.0 equiv.) in DMF (1.2M) was added EDC (1.0 equiv.) and HOBt (1.0 equiv.) followed by 3-trifluoromethylaniline (1.0 equiv.) and the reaction was stirred at ambient temperature for 48 h. The reaction mixture was partitioned between ethyl acetate and water. The separated organic layer was dried with sodium sulfate and concentrated under vacuo. The concentrated crude was purified via silica gel chromatography and eluted with 0 to 100% ethyl acetate in heptanes to give 3-bromo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide in 83% yield. LCMS (m/z) (M+H)=358/360, Rt=1.1 min.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N:20]1([C:29]([C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>CN(C=O)C.O>[N:20]1([C:29]([C:31]2[CH:32]=[CH:33][C:34]([CH2:35][N:10]3[C:11]4[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=4[N:8]=[CH:9]3)=[CH:37][CH:38]=2)=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(CCl)cc1)n1ccc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)n3ccc4ccccc43)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 54.5 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-[(1-indolyl)carbonyl]benzyl chloride (2.70 g) and the mixture was stirred at room temperature for 22 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off to provide the title compound as colorless powder (2.25 g, 54%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[C:24]([NH2:26])[N:23]=[CH:22][N:21]=2)=[CH:18][N:17]=[CH:16][N:15]=1.NC1N=C[C:31]2[N:36]=[CH:35][N:34]=[CH:33][C:32]=2N=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH3:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[C:24]([NH:26][C:2]3[CH:3]=[CH:4][C:32]([CH2:31][N:36]4[CH2:35][CH2:9][O:8][CH2:7][CH2:6]4)=[CH:33][N:34]=3)[N:23]=[CH:22][N:21]=2)=[CH:18][N:17]=[CH:16][N:15]=1
Reactant: Nc1ncc2ncncc2n1
Reactant: COc1cc(OC)c(Cl)c(Nc2ncncc2-c2cc(N)ncn2)c1C
Product: COc1cc(OC)c(Cl)c(Nc2ncncc2-c2cc(Nc3ccc(CN4CCOCC4)cn3)ncn2)c1C

Procedure:
Compound 32 is carried out the same reaction as in Scheme 1 for compound 10 to afford N4′-(2-Chloro-3,5-dimethoxy-6-methyl-phenyl)-N6-(5-morpholin-4-ylmethyl-pyridin-2-yl)-[4,5′]bipyrimidinyl-6,4′-diamine as final product.
Reaction SMILES: O.[NH2:2][NH2:3].Br[C:5]1[S:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][N:9]=1>C(O)C>[NH:2]([C:5]1[S:6][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][N:9]=1)[NH2:3]
Reactant: CC(C)(C)c1nnc(Br)s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nnc(NN)s1
Yield: 79.6 %

Procedure:
Hydrazine hydrate (12.5 g) was added to a solution of 2-bromo-5-t-butyl-1,3,4-thiadiazole (22.1 g) in ethanol (100 ml), and the mixture was heated under reflux for 2 hours. The solvent was evaporated to give an oily solid which was crystallised from water to give 2-hydrazino-5-t-butyl-1,3,4-thiadiazole (13.7 g, 79%) as white needles, mp 111°-112° C.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18]N)[CH:13]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C[O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[CH2:28][CH2:27]2)=[O:23]>>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]3[C:28]4[CH2:27][C:26]5[C:30](=[CH:31][CH:32]=[C:24]([C:22]([OH:23])=[O:21])[CH:25]=5)[C:29]=4[NH:18][C:14]=3[CH:13]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(-c2cccc(NN)c2)cc1
Reactant: COC(=O)c1ccc2c(c1)CCC2=O
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2)-c2ccc(C(=O)O)cc2C4)cc1

Procedure:
By reacting (4′-Butyl-biphenyl-3-yl)-hydrazine hydrochloride (example 70, step 1) and 1-oxo-indan-5-carboxylic acid methyl ester as described in example 1 followed by hydrolysis as described in example 2 the title material is obtained in similar yield. ESMS m/z 382.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:22](O)(=O)C.C(N)=N>CCO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([F:12])[C:7]2[N:11]=[CH:22][NH:10][C:8]=2[CH:9]=1)=[O:21]
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1Cl
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acid methyl ester 6a (0.125 g, 0.404 mmol) is suspended in EtOH (2 mL) and formamidine acetate (63 mg, 0.605 mmol) is added. The reaction mixture is heated to reflux. After 16 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with water, saturated NaHCO3, 10% K2CO3 and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 0.109 g (85%) pure desired product.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O.[CH3:23]O>C1COCC1>[CH3:23][O:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 86 %

Procedure:
Concentrated sulfuric acid (approximately 4 ml) was carefully added to a solution of 4'-hydroxy-4-biphenylcarboxylic acid (Aldrich) (8.20 g, 38.3 mmol) in 1 liter of methanol. The reaction mixture was refluxed for three days and the solvent was evaporated. The resulting solid was filtered, washed with water, and recrystallized as follows. The crude solid was dissolved in a minimum amount of hot THF, and approximately three equivalents of methanol was added to the solution. The solution was brought to a boil, and water was added with vigorous stirring until the solution remained cloudy. After cooling, the tan precipitate was filtered, washed with cold ethanol, and air dried to yield 7.57 g (86%) of a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=O)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[Li][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH:14]([C:17]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)[OH:19])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1
Reactant: [Li]c1cccs1
Reactant: COC(=O)C1CCN(CCc2ccc(OC)cc2)CC1
Solvent: C1CCOC1
Product: COc1ccc(CCN2CCC(C(O)(c3cccs3)c3cccs3)CC2)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Dissolve 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester (4.0 g, 14.42 mmol) in anhydrous tetrahydrofuran (100 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, 2-lithiothiophene (14.42 mL of a 1M solution in tetrahydrofuran, 14.42 mmol) and stir at -78° C. for 3 hours. Add additional 2-lithiothiophene (14.42 mL of a 1M solution in tetrahydrofuran, 14.42 mmol) and stir at -78° C. for 2 hours. Remove the ice bath and allow to warm to room temperature. Quench with saturated ammonium chloride (100 mL), separate the organic phase and extract the aqueous phase with ethyl acetate. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (ethyl acetate) and recrystallize (ethyl acetate) to give the title compound as fluffy white crystals; mp 153°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:24])[NH2:23].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[CH:29]=[CH:30][C:25]([C:22](=[O:24])[NH2:23])=[CH:26][CH:27]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C(N)=O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester and 4-carbamoylphenyl boronic acid (2 eq.) were coupled in 7:2 toluene-H2O with Na2CO3 (3 eq.) and Pd(PPh3)4 (0.1 eq.). After heating for 4 hours at 80° C., the reaction mixture was purified by flash chromatography to provide (S)-2-tert-butoxycarbonylamino-3-(4′-carbamoyl-biphenyl-4-yl)-propionic acid methyl ester. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was treated with excess NEt3 in DCM to produce a free amine. The free amine was coupled with 2,5-dimethyloxazole-4-carboxylic acid (2 eq.) in dry DCM with HBTU (2.2 eq.) and NEt3 (3 eq.). After reacting for 2 hours at room temperature, the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed according to general procedure B to give the title compound (11 mg). LCMS (m/z) 876.