Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C@H:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][OH:6].Cl[CH2:11][C:12](Cl)=[O:13].[NH4+].[Cl-]>C1(C)C=CC=CC=1.O>[CH3:8][CH:7]([C@H:4]1[NH:3][C:12](=[O:13])[CH2:11][O:6][CH2:5]1)[CH3:9]
Reactant: CC(C)[C@@H](N)CO
Reactant: O=C(Cl)CCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)[C@@H]1COCC(=O)N1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 67.2 %

Procedure:
NaH (6.24 g, 60% wt in mineral oil, 156 mmol, 2.3 equiv) was charged into a 1 L RB flask, followed by addition of 100 mL of toluene. The suspension was stirred in an ice bath. (2R)-2-Amino-3-methyl-1-butanol (7.0 g, 67.9 mmol) in 50 mL of toluene was added portion-wise. Addition took 10 minutes, followed with removal of the cooling bath. The mixture was stirred at ambient temperature for 15 minutes, and cooled in an ice bath. To the cooled mixture was added portion-wise a solution of chloroacetyl chloride (6.25 mL, 78 mmol, 1.15 equiv) in 50 mL of toluene. The mixture began to foam. When the addition neared completion, foaming subsided. The resulting mixture was heated under a reflux condenser to 90° C. (oil bath temp) for 20 hours. The mixture was cooled to room temperature, followed by addition of 22 g of NH4Cl and then water (50 mL). The phases were separated. The aqueous phase was extracted with EtOAc (2×150 mL). The combined organic was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated in 30 mL of hexane. The solids formed were collected by filtration, washing with hexane (2×10 mL). Drying under vacuum at room temperature for 5 hours gave the title compound (6.53 g) as a cream-colored solid. LC-MS (ES) m/z=144
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6]=1[CH3:15])=[O:4].[OH-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1c(C)[nH]c2ncc(Cl)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 19.2 %

Procedure:
A cooled (0-5° C.) suspension of 5-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (57 g, 0.25 mol), powdered sodium hydroxide (30.45 g, 0.76 mol) and benzyltriethylammonium chloride (1.16 g, 5.1 mmol) in dichloromethane (800 mL) was treated over ca. 5 minutes with benzenesulfonyl chloride (56.1 g, 40.5 mL, 0.32 mol). The reaction mixture was allowed to stir at 0-5° C. for 15 minutes then allowed to warm to ambient temperature and stirred for 24 hours. The solid was removed by filtration through celite and the cake washed with dichloromethane. The filtrate was evaporated and the resultant residue triturated with diethyl ether to afford the title compound as a brown solid (17.5 g, 30%). LCMS (Method B): RT=4.67 min, M+Na+=381. 1H NMR (400 MHz, CDCl3): 8.34 (d, J=2.4 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 8.18-8.18 (m, 2H), 7.61-7.61 (m, 1H), 7.51-7.50 (m, 2H), 3.94 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (400 mg; 0.96 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The solution is cooled down to 0° C. and put under nitrogen. Triethylamine (0.54 ml; 1.92 mmol; 4 eq) and 1-Boc-piperazine (358.4 mg; 1.92 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 1 hour. The reaction mixture is washed with water, NaHCO3 and dried over MgSO4, affording the title compound (440 mg; 76%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)C(O)=O)=[N:4][NH:3]1.[N:22]1([C:29](OC(C)(C)C)=[O:30])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[N:22]1([C:29]([C:15]2[CH:14]=[C:13]([CH:21]=[CH:20][CH:19]=2)[CH2:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][N:4]=2)=[O:30])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: O=C(c1cccc(Cc2n[nH]c(=O)c3ccccc23)c1)N1CCCNCC1
Yield: 97 %

Procedure:
The synthesis was carried out according to the method described in (a) above using 3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)benzoic acid (A) and tert-butyl 1-homopiperazine carboxylate to yield 4-[3-([1,4]diazepane-1-carbonyl)benzyl]-2H-phthalazin-1-one (3) as a grey crystalline solid (5.3 g, 97%); m/z [M+1]+ 363 (97% purity); δH 2.6-3.8 (10H, m), 4.4 (2H, s), 7.2-7.5 (4H, m), 7.7-8.0 (3H, m), 8.2-8.3 (1H, m), 12.6 (1H, s)
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24]([N:26]3[CH2:29][CH:28]([O:30][C:31]4[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=4)[CH2:27]3)=[O:25])=[N:21][N:20]=2)=[CH:15][CH:14]=1.[Na].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:2]1[C:6]2([CH2:10][CH2:9][N:8]([CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH:28]4[CH2:29][N:26]([C:24]([C:22]5[O:23][C:19]([C:16]6[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=6)=[N:20][N:21]=5)=[O:25])[CH2:27]4)=[CH:38][CH:37]=3)[CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1COC2(C1)CCNC2
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4)C3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(CN5CCC6(CCCO6)C5)cc4)C3)o2)cc1
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
1-oxa-7-azaspiro[4.4]nonane hydrochloride (65 mg, 0.40 mmol) and TEA (0.082 mL, 0.59 mmol) were mixed with DCM (4 mL). To the mixture was added 4-(1-(5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.150 g, 0.40 mmol) dissolved in DCM (1 mL). After stirring for 10 min, sodium triacetoxyhydroborate (0.168 g, 0.79 mmol) was added and the reaction mixture was stirred at RT overnight. An aqueous solution of NaHCO3 (8%, 10 mL) was added and the mixture was extracted twice with DCM (15 mL). The organic layer was dried over a phase separator and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (25 g) eluting with a mixture of EtOAc and ammonia in MeOH (2M) 20:1. The pooled fractions were concentrated under reduced pressure yielding the desired compound as a white solid (95 mg, 49%). 1H NMR (400 MHz, CDCl3): δ 1.73 (m, 5H), 1.86 (m, 1H), 2.57 (m, 3H), 2.69 (m, 1H), 3.56 (m, 2H), 3.77 (m, 2H), 3.88 (s, 3H), 4.32 (dd, 1H), 4.63 (m, 1H), 4.73 (dd, 1H), 5.07 (m, 2H), 6.71 (d, 2H), 7.01 (d, 2H), 7.27 (d, 2H), 8.09 (d, 2H). MS (APCI+) m/z 491.5 [M+H]+. LC purity: 94%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N+:24](C1C=CC(C(ON)=O)=CC=1)([O-])=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[NH2:24])=[O:4]
Reactant: NOC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC(=O)OC(C)(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(N)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 57.8 %

Procedure:
To a solution of 3-tert-butoxycarbonylamino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (4.3 g, 12.8 mmol) in NMP (64 mL) was added K-OtBu (1.6 g, 14.1 mmol). After 10 min a solution of O-4-nitrobenzoylhydroxylamine (3.0 g, 16.6 mmol) in NMP (16 mL) was added dropwise and the reaction was allowed to stir for 16 h. The reaction was quenched with LiCl solution (5% in water, 50 mL) and diluted with EtOAc (50 mL). The crude product was washed 3×50 mL with 5% LiCl solution, dried over Na2SO4, and purified by silica gel chromatography 0-30% EtOAc/hexanes to give 3-(N-tert-butoxycarbonyl-hydrazino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.6 g, 7.4 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:26])[CH3:2].[CH2:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[C:29]#[CH:30].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:30]#[C:29][CH2:28][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:17]=[C:18]([O:20][CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:26])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CC3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.55 mmol) and 4-prop-2-ynyl-morpholine (208 mg; 1.7 mmol) applying the procedure described for {4-[3-[2-(4-Chlorophenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 205 mg; 75%. HPLC-MS: m/z: 496.1 (M+H)+; Rt: 2.04 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=1)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=1
Reactant: COC(=O)CCC(=O)c1ccc(CCO)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCc1ccc(CCO)cc1
Reaction time: 12 h
Yield: 37.6 %

Procedure:
A mixture of Example 1A (2.50 g, 11 mmol), 10% Pd/C (0.25 g, 0.23 mmol of Pd metal) in anhydrous methanol (25 mL) was first degassed to remove air (two vacuum/H2 cycles) after which it was capped and a balloon filled with H2 was applied to it for 12 hours. After this time the reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to give 2.32 g of crude material. Column chromatography [silica gel; eluent hexanes-ethyl acetate (2:1)] provided the desired product (0.92 g, 39%). 1H (CDCl3) δ(ppm): 1.91-1.96 (m, 2H); 2.32 (t, 2H); 2.62 (t, 2H); 2.83 (t, 2H); 3.66 (s, 3H); 3.85 (t, 2H); 7.11-7.15 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:26])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH2:19][C:18]=3[C:24]=2[CH3:25])=[CH:4][CH:3]=1.[OH:27]O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:15]([CH3:26])=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][CH2:19][C:18]=3[C:24]=2[CH3:25])=[O:27])=[CH:6][CH:7]=1
Reactant: Cc1ccc(SCCCCOc2c(C)cc3c(c2C)COC(=O)N3)cc1
Reactant: OO
Product: Cc1ccc(S(=O)CCCCOc2c(C)cc3c(c2C)COC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-methylphenylmercapto)-butoxy]-5,7-dimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:35])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:34][C:30]1[CH:29]=[C:28]([C:26]2[CH2:25][C:24](=[O:35])[NH:23][C:9]3[CH:10]=[C:11]([C:19]([F:22])([F:21])[F:20])[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:13][C:8]=3[N:7]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(Br)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CNc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(Br)c1)=N2

Procedure:
) The title compound was prepared from the above described {2-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-5-isobutylamino-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (1.03 g, 1.8 mmol) and TFA (7 mL) in DCM (20 mL) according to general procedure I step 2. Obtained as a light yellow solid (0.75 g, 92%). MS (ISP) 454.3 [(M+H)+]; mp 217° C. (dec).
Reaction SMILES: [F:1][C:2]([F:10])([C:6]([F:9])([F:8])[CH3:7])[CH:3]([OH:5])O.N1C=CC=CC=1.[F:17][C:18]([F:31])([F:30])[S:19]([O:22]S(C(F)(F)F)(=O)=O)(=[O:21])=[O:20]>ClCCl>[F:8][C:6]([F:9])([C:2]([F:10])([F:1])[CH2:3][O:5][S:19]([C:18]([F:31])([F:30])[F:17])(=[O:21])=[O:20])[CH2:7][O:22][S:19]([C:18]([F:31])([F:30])[F:17])(=[O:20])=[O:21]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(F)(F)C(F)(F)C(O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 2,2,3,3-tetrafluorobutanediol (15 g, 93 mmol) and pyridine (19 mL, 230 mmol) in dichloromethane (250 mL), was added dropwise trifluoromethanesulfonic anhydride (34 mL, 200 mmol). After the addition, the mixture was stirred at 0° C. for one hour, followed by stirring at room temperature for one additional hour, then diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to near dryness, leaving a dichloromethane-containing oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:32][OH:33])([CH2:30][OH:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=1)(C)(C)C.O1CCOCC1.[ClH:41]>C(Cl)Cl>[ClH:41].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:27])([F:28])[F:29])[CH:12]=1)([CH2:30][OH:31])[CH2:32][OH:33]
Reactant: CCCCCCCCOc1ccc(CCC(CO)(CO)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Compound 9-7 (490 mg) was dissolved in methylene chloride (5 ml), dioxane containing hydrogen chloride (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (350 mg) as a white powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>C(O)(C)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([CH2:28][CH2:27][N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(CCN2CCOCC2)c1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
2-[(2,5-dichloro-4-pyrimidinyl)amino]-N,N-dimethylbenzamide (300 mg, 0.96 mmol), 3-[2-(4-morpholinyl)ethyl]aniline (198 mg, 0.96 mmol) were combined in a vessel with 10 mL of isopropanol and TFA (74 μL, 0.96 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction mixture was concentrated to dryness. The crude product was purified via semi-preparative HPLC to afford the title compound as a white solid (83 mg, 18%): Mass (M+H)+=481, 483.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[CH2:12][C:11]([N:23]([CH3:25])[CH3:24])=[N:10]2)=[CH:5][CH:4]=1.[BrH:26]>>[BrH:26].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[CH2:12][C:11]([N:23]([CH3:25])[CH3:24])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)C(c1ccc(Cl)cc1)N=C(N(C)C)C2
Agent: Br
Agent: Cl
Product: CN(C)C1=NC(c2ccc(Cl)cc2)c2cc(O)c(O)cc2C1

Procedure:
A solution of 1-(4-chlorophenyl)-3-dimethylamino-6,7-dimethoxy-1,4-dihydroisoquinoline hydrochloride (1.3 g) in 48% aqueous hydrobromic acid (100 ml) was heated at 100°-120° C. under nitrogen for 3 h. The hot solution was filtered, and the filtrate evaporated to dryness in vacuo and recrystallised from ethanol-ether, to give 1-(4-chlorophenyl)-6,7-dihydroxy-3-dimethylamino-1,4-dihydroisoquinoline hydrobromide (1.07 g), m.p. 232°-235° C.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)(C)C)(C)(C)C.C([Li])(CC)C.CN(C)[CH:24]=[O:25].Cl>O1CCCC1.O.CCOCC>[Cl:16][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[CH:24]=[O:25]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -68 °C

Procedure:
Dissolve tert-butyl-(3,5-dichloro-phenoxy)-dimethyl-silane (425 g, 1.5 mol) in 4 L dry tetrahydrofuran and cool to −68° C. Slowly add 1.1 equivalents of sec-butyl lithium (103.1 g, 1.61 mol) at −68° C. (˜1.75 hr). After addition is complete, stir the reaction at −70° C. for 30 min. Add dimethylformamide (168.5 g, 2.3 mol) and stir the reaction at −70° C. for 1 hr. Add 1 M hydrochloric acid in water (3.5 L) and allow the reaction to warm to room temperature. Pour the reaction mixture into ether (5 L), wash with water then brine. Dry over sodium sulfate and concentrate under vacuum to an orange solid. Triturate with cold dichloromethane and filter to recover 250 g (80%) pale yellow solid.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)[CH2:8][O:7][CH2:6][C:5]=12.C([Sn](=O)CCCC)CCC.C[Si]([N:32]=[N+:33]=[N-:34])(C)C>C1(C)C=CC=CC=1>[NH:32]1[C:14]([C:13]2[CH:16]=[CH:17][C:10]([CH:9]3[CH2:8][O:7][CH2:6][C:5]4=[CH:1][N:2]=[CH:3][N:4]34)=[CH:11][CH:12]=2)=[N:15][N:34]=[N:33]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccc(C2COCc3cncn32)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: c1cc(C2COCc3cncn32)ccc1-c1nnn[nH]1
Temperature: 125 °C

Procedure:
A solution of 0.17 mmol of 4-(5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)benzonitrile (Example 1) and 0.017 mmol of dibutyltin oxide in 4.0 ml of toluene is mixed with 3.34 mmol of trimethylsilyl azide. The reaction mixture is heated at 125° C. overnight. It is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][N:6]([CH3:15])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[CH:9][N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([N:6]([CH3:15])[CH3:5])=[N:8][CH:9]=1)=[C:1]=[S:2]
Reactant: Cc1cc(N(C)C)ncc1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)ncc1N=C=S
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
Thiophosgene (9.3 mL, 125 mmol) was added dropwise to a stirred mixture of N2,N2,4-trimethylpyridine-2,5-diamine (15.7 g) in tetrahydrofuran (100 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a colorless powder (14.1 g, 73.0 mmol, 70% in 2 steps).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[C:22]1([S:32]([O-:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.[Na+]>>[C:22]1([S:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:34])=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=S([O-])c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)c4cccc5ccccc45)cc3c2C1
Yield: 26 %

Procedure:
The product of Example 29, step B and sodium 1-naphthylsulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 75:25 hexane/ethyl acetate) provided tert-butyl 8-(1-naphthylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (76 mg, 26%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 8.67 (d, J=8.1 Hz, 1H), 8.51 (dd, J=7.5, 1.2 Hz, 1H), 8.18-8.01 (m, 2H), 7.92-7.76 (m, 2H), 7.67-7.41 (m, 4H), 4.58-4.47 (m, 2H), 3.81 (br s, 2H), 2.83 (br s, 2H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4]Cl.[CH2:13]([OH:16])[CH2:14][OH:15]>>[OH:15][CH2:14][CH2:13][O:16][CH2:4][C:3]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Reactant: OCCO
Product: O=[N+]([O-])c1ccc(O)c(COCCO)c1

Procedure:
6.5 moles (93.8 g) of 2-hydroxy-5-nitrobenzyl chloride are heated for 4 hours in 150 ml of ethylene glycol on a boiling water bath. The expected product crystallizes after dilution of the reaction mixture with a litre of iced water. After filtering off followed by drying at 40° C. under air vacuum the product obtained is recrystallized from isopropyl acetate. It melts at 132° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:24].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:9]1[C:10]2[C:16]3[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:24])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccc([N+](=O)[O-])cc43)c2=O)c(OC)c1
Reactant: BrCc1ccccc1
Product: O=c1c2sc3ccc([N+](=O)[O-])cc3c2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-8-nitro-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with benzyl bromide and subsequently deprotected to provide the title compound as a light yellow solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.77 (s, 2H); 7.24-7.40 (m, 5H), 8.29 (dd, J1=9 Hz, J2=2 Hz, 1H); 8.40 (d, J=9 Hz, 1H); 8.71 (d, J=2 Hz, 1H); Ret. time=2.56 min., m/z=368.0.