Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([NH:30]C(OCC5C=CC=CC=5)=O)[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[K+].CCCCCC.CCOC(C)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([NH2:30])[CH:26]=[CH:27][C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Sc2ccc(CN3CCC(c4cc(NC(=O)OCc5ccccc5)ccc4C)CC3)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Sc2ccc(CN3CCC(c4cc(N)ccc4C)CC3)cc2)cc1
Temperature: 100 °C
Yield: 98.2 %

Procedure:
N-[3-(1-{[4-(4-methoxyphenylthio)phenyl]methyl}(4-piperidyl))-4-methylphenyl](phenylmethoxy)carboxamide (486 mg, 0.881 mmol) was dissolved in methanol (10.0 mL) and an aqueous KOH solution (40%, 1.20 mL) was added. The reaction mixture was heated at 100° C. for 10 h. After cooling to room temperature, the reaction mixture was poured into a separatory funnel. The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (eluent: Hexane:EtOAc (1:1 then 1:4)) gave the desired product (362 mg, 98.2% yield). 1H NMR (CDCl3) δ 7.43-7.35 (m, 4H), 7.24-7.11 (m, 3H), 6.93-6.85 (m, 2H), 6.63-6.58 (m, 1H), 6.48-6.42 (m, 1H), 3.82 (s, 3H), 3.48 (s, 2H), 3.03-2.91 (m, 2H), 2.68-2.54 (m, 1H), 2.20 (s, 3H), 2.13-1.98 (m, 2H), 1.79-1.64 (m, 4H). ESMS m/e: 419.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[C:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)(O)=[O:16]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (30 mg) and 4-carboxybenzenesulfonamide to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminosulfonyl)-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[CH:7]=[C:6]([NH2:11])[C:5]=1[N+:12]([O-:14])=[O:13].[CH2:16](N(CC)CC)C.[CH3:23][CH2:24][O-:25].[Na+]>C(O)C>[CH2:1]([O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:25][CH2:24][CH3:23])[CH:7]=[C:6]([NH2:11])[C:5]=1[N+:12]([O-:14])=[O:13])[CH3:16]
Reactant: CC[O-]
Reactant: COC(=O)c1cc(F)cc(N)c1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(OCC)cc(N)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
5.0 g (23.3 mmol) of 3-amino-5-fluoro-2-nitro-benzoic acid methyl ester was dissolved in ethanol and treated with 2.6 g (25.6 mmol) of triethylamine and 1.8 g (25.6 mmol) of NaOEt. The reaction was heated at 60° C. for 0.5 h to produce 3-amino-5-ethoxy-2-nitro-benzoic acid ethyl ester. LCMS: 255 (M+1)+.
Reaction SMILES: [CH2:1]([O:4]C(N1CC=C(C2C(C3C=CN=C(F)C=3)=C(C3C=CC(F)=CC=3)NC=2)CC1)=O)[CH:2]=C.C(O[C:40]([N:42]1[CH2:49][C:48]([F:51])([F:50])[CH2:47][C@H:43]1[C:44](O)=O)=O)C1C=CC=CC=1.C(OC(N1C[C@H](OC)C[C@H]1C(O)=O)=O)C1C=CC=CC=1>>[F:51][C:48]1([F:50])[CH2:49][N:42]2[C@@H:43]([CH2:44][C:1](=[O:4])[CH2:2][CH2:40]2)[CH2:47]1
Reactant: C=CCOC(=O)N1CC=C(c2c[nH]c(-c3ccc(F)cc3)c2-c2ccnc(F)c2)CC1
Reactant: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Product: O=C1CCN2CC(F)(F)C[C@@H]2C1

Procedure:
In a similar manner to the procedures described in Preparative Examples 1(i)′, (ii) and (iii) above, reactions were carried out successively, using (2S)-1-benzyloxycarbonyl-4,4-difluoroproline as a starting material instead of (2S,4R)-1-benzyloxycarbonyl-4-methoxyproline, to give the title compound as a pale yellow oil (total yield for the 3 steps: 14%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Si:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:30]=[CH:29][C:28]=1[CH:41]1[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClC(Cl)C>[CH:10]1([NH:16][C:17](=[O:18])[O:47][C@H:44]2[CH2:43][CH2:42][C@H:41]([C:28]3[CH:29]=[CH:30][C:31]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])=[CH:32][C:27]=3[O:26][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:46][CH2:45]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)NC3CCCCC3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C

Procedure:
N,N-Diisopropylethylamine (199 μl) and cyclohexyl isocyanate (128 μl) were added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated to 40° C. for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a pale yellow solid (30 mg, 47%); δH(CDCl3) 0.12 (6H, s), 0.18 (6H, s), 0.90 (9H, s), 0.95 (9H, s). 1.00-2.10 (18H, m), 2.70-2.80 (1H, m), 3.36-3.50 (1H, m), 4.40-4.48 (1H, m), 4.50-4.62 (1H, m), 6.20 (1H, d), 6.32 (1H, dd), 6.86 (1H, d).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=3)[C:4]=2[CH:3]=1.[CH2:30]([Li])CCC.CCCCCC.IC.Cl.[Cl-].[Na+]>O1CCCC1>[CH2:27]([CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=2)[C:4]2[CH:3]=[C:2]([CH3:30])[CH:15]=[CH:14][C:13]=2[N:12]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:28]
Reactant: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: [Li]CCCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: CCC1c2cc(F)ccc2-c2cc(C)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A stirred solution of 2-bromo-6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (Example 44, Step c, 0.30 g, 0.63 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C., and treated drop-wise under nitrogen with a solution of 1.4 M n-butyllithium in hexane (0.9 mL, 1.26 mmol). After stirring for 10 min, iodomethane (0.08 mL, 1.26 mmol) was added, and the reaction stirred until room temperature was reached. The reaction was quenched with a 0.1 N hydrochloric acid solution (15 mL, 1.5 mmol), and a saturated, aqueous, sodium chloride solution (150 mL). The separated aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product, which was used without further purification;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N:5]2.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.CCN(CC)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[N:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2](/[CH:30]=[CH:29]/[C:28]([O:32][CH3:33])=[O:31])[CH:3]=3)[N:8]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2nc3ccc(Br)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A solution of 6-bromo-2,3-bis(4-methoxyphenyl)quinoxaline (100 mg, 0.24 mmol, 1.00 equiv), methyl acrylate (40.8 mg, 0.47 mmol, 2.00 equiv), Pd(OAc)2 (5.3 mg, 0.02 mmol, 0.10 equiv), PPh3 (24.8 mg, 0.09 mmol, 0.40 equiv) in DMF/Et3N (4/2 mL). The resulting solution was stirred overnight at 100° C. under an inert atmosphere. The mixture was concentrated under vacuum and purified via silica gel column (ethyl acetate/petroleum ether (1:30)), yielding 80 mg (79%) of (E)-methyl 3-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)acrylate as a yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1C=CC=CC=1.N1CCCCC1>O>[C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH:1]=[CH:14][C:15]([OH:17])=[O:16])=[CH:4][CH:5]=1)([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C=CC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a 3-L three-necked round-bottom flask equipped with an overhead stirrer, condenser, and a nitrogen/thermocouple unit was added methyl p-formylbenzoate (82.08 g, 0.50 mole), malonic acid (104.06 g, 1.00 mole), and pyridine (200 mL). Stirring was started followed by heating to 50° C. for 75 minutes. By this time, a sizable amount of solids had formed and to this mixture was added piperidine (7.5 mL, 0.076 mole) and the temperature raised to 80° C. After another one hour at 80° C., the temperature was raised to 115° C. After another 2.5 hours at this temperature, heating was stopped and the mixture allowed to cool before pouring into water (2 L). To the aqueous mixture was carefully added concentrated HCI (250-300 mL) until the mixture became acidic. The mixture was filtered, and the solids washed with fresh water (1 L) before being suction dried. A yield of 96.83 g (93.9 percent) of white solids was obtained. Proton nmr (DMSO-d6) delta: 7.95 (2H, d); 7.80 (2H, d); 7.60 (1H, d); 6.62 (1H, d); 3.82 (3H, s).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH3:12].C([O-])([O-])=O.[Na+].[Na+].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>C1(C)C=CC=CC=1.O.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:7](=[O:8])[N:6]3[CH:9]=[CH:10][S:11][C:5]3=[N:4][C:3]=2[CH3:12])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Cc1nc2sccn2c(=O)c1I
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1

Procedure:
To a solution of Step 2 intermediate (0.300 g, 1.027 mmol) in toluene (10 ml) was added Pd[(C6H5)3P]4 [tetrakis(triphenylphosphine)palladium(0)] (0.048 g. 0.042 mmol) and a solution of Na2CO3 (0.653 g, 6.162 mmol) in water (4 ml). A solution of 3,5-difluorophenylboronic acid (6.5 g, 44.235 mmol) in ethanol (6 ml) was added to the reaction mixture and it was refluxed for 1.5 h. After completion of the reaction mixture, the solvent was concentrated in vacuo, the residue partitioned between ethyl acetate (200 ml) and water (50 ml). The organic layer was washed with brine (50 ml) and dried over anhydrous Na2SO4 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 280 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 7.53 (d, J=7.8 Hz, 3H), 7.88 (d, J=7.8 Hz, 1H) 8.02 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 276.31 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[C:20]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])#[CH:21].N1CCCC1>CN(C=O)C.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.[Cu]I>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][O:4][C:3]1[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:2]=1[C:21]#[C:20][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27].[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][O:4][C:3]1[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:2]=1[C:21]#[C:20][Si:22]([CH:23]([CH3:25])[CH3:24])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)[Si](C#Cc1cc(N)ccc1OCc1cccc(F)c1)(C(C)C)C(C)C
Product: CC(C)[Si](C#Cc1cc([N+](=O)[O-])ccc1OCc1cccc(F)c1)(C(C)C)C(C)C
Temperature: 80 °C

Procedure:
To a solution of 1-((2-bromo-4-nitrophenoxy)methyl)-3-fluorobenzene (1 g), ethynyltriisopropylsilane (1.032 mL), pyrrolidine (0.3 mL) in DMF (20 mL) was added Pd(PPh3)2Cl2 (501 mg), CuI (117 mg) and the mixture was heated at 80° C. overnight. The solvent was removed, the residue was purified by flash chromatography, eluting with 10% EtOAc in hexane to give the desired product (2-(2-(3-fluorobenzyloxy)-5-nitrophenyl)ethynyl)triisopropylsilane (compound 23.1, 472 mg) and 4-(3-fluorobenzyloxy)-3-(2-(triisopropylsilyl)ethynyl)benzenamine (compound 23.2, 440 mg). LCMS ESI(+) m/z: 428 (M+1) and LCMS ESI(+) m/z: 398 (M+1).
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[OH:38][Li].O>O.C1COCC1>[OH:1][C:2]1([C:29]2[S:33][C:32]([OH:38])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:4][CH2:3]1
Reactant: [Li]O
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cnc(O)s3)CC2)C1

Procedure:
A solution of N-({1-[4-Hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a, 100 mg, 0.18 mmol) and LiOH hydrate (Aldrich, 15 mg, 0.36 mmol) in water (1 mL) and THF (1 mL) was heated to 60° C. in a sealed tube for 2 hours. The crude solution was directly purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3c(Cl)ccc(Cl)c3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3,4-trichlorobenzene and isolated as white solid. MS (m/e): 475.3 (MH+).
Reaction SMILES: O.[NH2:2][NH2:3].I.[CH2:5]([N:12]([CH3:18])[C:13](=[N:16][CH3:17])OC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:19]([OH:21])C>>[CH2:5]([N:12]([CH3:18])[C:13]1[N:16]([CH3:17])[C:19](=[O:21])[NH:2][N:3]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN=C(OC)N(C)Cc1ccccc1
Reactant: NN
Reactant: CCO
Agent: I
Solvent: O
Product: CN(Cc1ccccc1)c1n[nH]c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Hydrazine hydrate (9.41 ml) was added to a mixture of 1-benzyl-1,2,3-trimethyl-isourea hydroiodide (CAS 56043-41-5) (65.2 g) and ethanol (400 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, pyridine (300 ml) was added to the residue, and ethyl chloroformate (20.4 ml) was added dropwise while stirring on ice. After heating to reflux for 1 hour and 30 minutes, the reaction mixture was concentrated under reduced pressure. After then adding N,N-dimethylformamide (452 ml) to the residue, the mixture was stirred at 150° C. for 17 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. The obtained solid was recrystallized from diethyl ether-n-heptane to obtain the title compound (17.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C=O)C>[Si:12]([O:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Oc1cn[nH]c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cn[nH]c1
Reaction time: 17 h
Yield: 94.3 %

Procedure:
4-Hydroxypyrazole (1.16 g, 13.8 mmol) and imidazole (1.13g, 16.6 mmol) were suspended in DMF (50 ml) under nitrogen and t-butyldimethylsilylchloride (2.3 g, 15.2 mmol) was added. After stirring 17 hours, the solvent was removed in vacuo and the residue treated with water containing 4.5 g of potassium carbonate. The mixture was extracted with two portions of chloroform and the organic layer dried over sodium sulfate. The solvent was removed in vacuo to yield product (2.58 g, 94%). NNR
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[OH:15])=[O:4].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:26])[CH3:25])=[CH:20][CH:19]=1.[CH2:27](N(CC)CC)C>CN(C=O)C.O>[CH2:1]([O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:26][CH:24]([C:21]3[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH3:25])[C:7]=2[C:6]=1[OH:15])=[O:4])[CH3:27]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1O
Reactant: COc1ccc(C(C)N)cc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2ncnc(NC(C)c3ccc(OC)cc3)c2c1O
Yield: 36 %

Procedure:
A stirred solution of 4-chloro-5-hydroxythieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.5 g, 1.9 mol), 1-(4-methoxyphenyl)ethylamine (0.4 g, 2.5 mol) and triethylamine (1 mL) in DMF (20 mL) was warmed to 60° C. for one hour. The reaction mixed was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was recrystallized from methylene chloride and hexane to give product (0.25 g, 0.7 mol, 36 percent) yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]=[C:26]1[CH2:35][CH2:34][CH2:33][C:32]2[C:31]([OH:36])=[CH:30][CH:29]=[CH:28][C:27]1=2>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:36][C:31]3[C:32]4[CH2:33][CH2:34][CH2:35][C:26](=[CH2:25])[C:27]=4[CH:28]=[CH:29][CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: C=C1CCCc2c(O)cccc21
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: C=C1CCCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 79.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol (43 mg, 0.26 mmol, example 39) to give the title compound (52 mg, 85%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1ccccc1CCN
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CCNC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Forty (40) grams of 4-bromobenzoic acid was dissolved in 200 ml of dry dimethylformamide. While the solution was cooled with ice with stirring, 23 g of triethylamine and 22 g of ethyl chloroformate were added. After a lapse of 30 minutes, 28 g of 1-amino-2-(2-methylphenyl)ethane was added dropwise. The mixture was stirred at room temperature for 1 hour and then at 50° to 60° C. for 1 hour, and poured into ice water. The crystals precipitated were washed in water, dried, and recrystallized from cyclohexane to afford 49 g of 1-(4-bromobenzoylamino)-2-(2-methylphenyl)ethane as colorless needles having a melting point of 101.5° to 103.0° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][C:4](=[O:12])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2c([nH]1)CCCC2
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2c(c(O)c1[N+](=O)[O-])CCCC2

Procedure:
A solution of 4-hydroxy-5,6,7,8-tetrahydrocarbostyril (1.70g; 0.0103 mole) and concentrated nitric acid (2.5 ml; d 1.42), in glacial acetic acid (10 ml) was heated at 100° C till the oxides of nitrogen were evolved and rapidly cooled in ice. Water (40 ml) was added to the red solution to precipitate the yellow-orance 3-nitro derivative. After filtration, thorough washing with water and recrystallisation from acetic acid - ethanol the product had m.p. 241° (d).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1.[B:16](OC)([O:19]C)[O:17]C.[OH-].[Na+]>CCCCCC.C(OCC)C.O>[CH3:15][O:14][CH2:13][C:11]1[CH:12]=[C:7]([B:16]([OH:19])[OH:17])[CH:8]=[N:9][CH:10]=1
Reactant: COCc1cncc(Br)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: COCc1cncc(B(O)O)c1
Temperature: -100 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
To a solution of n-butyl lithium in hexane (6 ml of a 1.6M solution) in diethyl ether (40 ml) at -100° C. under nitrogen was added dropwise 3-bromo-5-methoxymethylpyridine (1.2 g, 6 mmol) (WO 95/28400) in diethyl ether (20 ml). After stirring for 45 minutes at -100° C., trimethyl borate (1.1 ml, 9.8 mmol) was added and the reaction mixture stirred at -100° C. for an extra 75 minutes. Water was added followed by 4N aqueous sodium hydroxide when the temperature reached 10° C. The aqueous layer was decanted, acidified to pH 5 with 2N aqueous hydrochloric acid and extracted 5 times with dichloromethane. The combined organics were dried (sodium sulphate) and evaporated to give the title compound as an oil (100 mg, 10%). MS, m/z 168 for (M+H)+. Rf 0.05 in ammonia/methanol/dichloromethane (1/10/90) on silica plate.